Urea Derivative Or Pharmacologically Acceptable Salt Thereof

ABSTRACT

Provided is a compound having a formyl peptide receptor like 1 (FPRL1) agonist effect. 
     The present invention relates to a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof. The present invention also relates to a pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/580,909 filed Sep. 24, 2019 which is a continuation of U.S.application Ser. No. 16/270,363, filed Feb. 7, 2019, which is acontinuation of U.S. patent application Ser. No. 16/011,050, filed Jun.18, 2018, now U.S. Pat. No. 10,252,992, which is a continuation of U.S.patent application Ser. No. 15/724,002, filed Oct. 3, 2017, now U.S.Pat. No. 10,029,983, which is a continuation of U.S. patent applicationSer. No. 15/039,964, filed May 27, 2016, now U.S. Pat. No. 9,822,069,which is a 371 application of PCT/JP2014/005933 filed Nov. 27, 2014,which is entitled to priority pursuant to 35 U.S.C. § 119(e) and 365(c)to Japanese patent application No. 2013-245502, filed Nov. 28, 2013,each of which is fully incorporated herein in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Sep. 22, 2019, isnamed 082867_000285_SL.TXT and is 4,418 bytes in size.

TECHNICAL FIELD

The present invention relates to a urea derivative or apharmacologically acceptable salt thereof that are useful aspharmaceuticals and have a formyl peptide receptor like 1 (hereinaftermay be abbreviated as FPRL1) agonist effect, to a pharmaceuticalcomposition containing the urea derivative or the pharmacologicallyacceptable salt thereof, and to a pharmaceutical use thereof.

BACKGROUND ART

FPRL1 (formyl peptide receptor like 1, also known as Lipoxin A4Receptor, ALXR, and FPR2) is a G protein-coupled receptor cloned as asubtype of N-formyl peptide receptors (FPRs) by Murphy et al.(Non-Patent Literature 1). The FPRL1 was discovered as a receptor thatmediates calcium mobilization in response to high concentration of fMLF(formyl methionine leucyl phenylalanine peptide).

Expression of FPRL1 has been found in neutrophils, monocytes,T-lymphocytes, dendritic cells, etc. (Non-Patent Literature 2), but therole of FPRL1 in a living body is complicated and has therefore not beenelucidated sufficiently (Non-Patent Literature 3). However, in a pawedema model and an arthritis model using FPRL1 deficient mice, it hasbeen recognized that the reactions become worse (Non-Patent Literature4). Therefore, it is considered that FPRL1 contributes to the resolutionof the inflammation.

Endogenous lipid mediators such as LipoxinA4 (LXA4) and Resolvin D1(RvD1) and peptides such as WKYMVm have been reported as agonists thatbind to FPRL1 (Non-Patent Literatures 5 and 6).

Such FPRL1 agonists can reduce neutrophil chemotaxis in vitro(Non-Patent Literatures 7 and 8). Although neutrophils perform hostdefense, they cause vascular injury, result in an increase in vascularpermeability and edema, followed by release of chemotactic factors, andthereby contribute to inflammation (Non-Patent Literature 9). Therefore,it is considered that the FPRL1 agonists exhibit an anti-inflammatoryeffect.

For example, it has been confirmed that peptide agonists exhibit aninhibitory effect on intestinal inflammation (Non-Patent Literature 10),an inhibitory effect on airway inflammation (Non-Patent Literature 11),an inhibitory effect on septicemia (Non-Patent Literature 12), and aninhibitory effect on a cancer model (Non-Patent Literature 13) It hasalso been recognized that QuinC1, a non-peptide low-molecular weightcompound, inhibits bleomycin-induced lung inflammation (Non-PatentLiterature 14).

Therefore, FPRL1 can be considered as a target of various diseases suchas inflammatory diseases, chronic airway diseases, cancers, septicemia,allergic symptoms, HIV retrovirus infection, circulatory disorders,neuroinflammation, nervous disorders, pains, prion diseases,amyloidosis, and immune disorders. Therefore, the FPRL1 agonists can bepromising therapeutic agent for these diseases.

Known examples of the non-peptide low-molecular weight compoundexhibiting FPRL1 agonist activity include quinazolinones (Non-PatentLiterature 15), pyrazolones (Non-Patent Literature 16), benzimidazoles(Non-Patent Literature 17), aminoazoles (Patent Literatures 1, 2, 3, 4,and 5), spiro[2,4]heptanes (Patent Literature 6), pyridazinones(Non-Patent Literature 18), cycloalkyl and cycloalkenyl-1,2-dicarboxylicacids (Patent Literature 7), dihydronaphthalenes (Patent Literature 8),pyrrolidine-2,5-diones (Patent Literature 9), and phenyl ureaderivatives (Patent Literatures 10, 11, 12, and 13) (Non-PatentLiteratures 19 and 20).

However, the basic chemical structures of these compounds are differentfrom those of the compounds of the present invention. It will beappreciated that the above compounds are not included in the claims ofthe present application.

CITATION LIST Non-Patent Literature

-   Non-Patent Literature 1: Murphy P. M., et al., “The Journal of    Biological Chemistry,” 1992, vol. 267, pp. 7637-7643-   Non-Patent Literature 2: Gavins F. N. E, et al., “Trends in    Pharmacological Sciences,” 2010, vol. 31, pp. 266-276-   Non-Patent Literature 3: Cattaneo F., et al., “International Journal    of Molecular Sciences,” 2013, vol. 14, No. 4, pp. 7193-7230-   Non-Patent Literature 4: Dufton N, et al., “The Journal of    Immunology,” 2010, vol. 184, pp. 2611-2619-   Non-Patent Literature 5: Le Y, et al., “Trends in immunology,” 2002,    vol. 23, No. 11, pp. 541-548-   Non-Patent Literature 6: Krishnamoorthy S, “Proceedings of the    National Academy of Sciences,” 2010, vol. 107, No. 4, pp. 1660-1665-   Non-Patent Literature 7: Li B. Q, et al., “Blood,” 2001, vol. 97,    pp. 2941-2947-   Non-Patent Literature 8: Sogawa Y, et al., “Immunology,” 2011,    1416974161282, pp. 441-450-   Non-Patent Literature 9: Summers C, et al., “Trends in Immunology,”    2010, vol. 31, pp. 318-324-   Non-Patent Literature 10: Kim S. D, et al., “Experimental &    Molecular Medicine,” 2013, vol. 13, No. 45: e40.-   Non-Patent Literature 11: Tae Y. M, et al., “The Journal of    Immunology,” 2012, vol. 188, pp. 1799-808-   Non-Patent Literature 12: Kim S. D, et al., “The Journal of    Immunology,” 2010, vol. 185, pp. 4302-4310-   Non-Patent Literature 13: Kim S. D, et al., “PLoS ONE,” vol.-   7, No. 1: e30522.-   Non-Patent Literature 14: MinH. E, et al., “Acta Pharmacologica    Sinica” 2011, vol. 32, pp. 601-610-   Non-Patent Literature 15: Nanamori M, et al., “Molecular    Pharmacology,” 2004, vol. 66, pp. 1213-1222-   Non-Patent Literature 16: Burli R. W, et al., “Bioorganic &    Medicinal Chemistry Letters,” 2006, vol. 16, pp. 3713-3718-   Non-Patent Literature 17: Frohn M, et al., “Bioorganic &Medicinal    Chemistry Letters,” 2007, vol. 17, pp. 6633-6637-   Non-Patent Literature 18: Cilibrizzi A, et al., “Journal of    Medicinal Chemistry,” 2009, vol. 52, pp. 5044-5057-   Non-Patent Literature 19: Kirpotina L. N, et al., “Molecular    Pharmacology,” 2010, vol. 77, pp. 159-170-   Non-Patent Literature 20: Schepetkin I. A, et al., “Molecular    Pharmacology,” 2011, vol. 79, pp. 77-90

PATENT LITERATURE

-   Patent Literature 1: WO2009/077990-   Patent Literature 2: WO2009/077954-   Patent Literature 3: WO2010/143158-   Patent Literature 4: WO2012/077049-   Patent Literature 5: WO2012/077051-   Patent Literature 6: WO2012/066488-   Patent Literature 7: WO2011/163502-   Patent Literature 8: WO2012/125305-   Patent Literature 9: US130018067-   Patent Literature 10: WO2005/047899-   Patent Literature 11: WO2012/074785-   Patent Literature 12: WO2012/109544-   Patent Literature 13: WO2013/062947

SUMMARY OF INVENTION Technical Problem

At present, no compound has been found which has a superior FPRL1agonist effect as a prophylactic or therapeutic agent for variousdisease states described above and can be used as a sufficientlysatisfactory pharmaceutical.

It is an object of the present invention to provide a compound having anFPRL1 agonist effect.

Solution to Problem

The present inventors have conducted extensive studies and found that aurea compound represented by the general formula (I) below (thiscompound may be referred to as a compound (I)) or a pharmacologicallyacceptable salt thereof has a superior FPRL1 agonist effect and issufficiently satisfactory as a pharmaceutical, and thus the presentinvention has been completed.

Accordingly, the present invention is as follows.

[1] A compound represented by the general formula (I) or apharmacologically acceptable salt thereof:

[wherein, in the formula (I), Ar¹ is a phenyl group optionally havingsubstituent(s), a 5-membered aromatic heterocyclic group optionallyhaving substituent(s), a 6-membered aromatic heterocyclic groupoptionally having substituent(s), or a bicyclic aromatic heterocyclicgroup having 8 or 9 atoms and optionally having substituent(s);

Ar² is a phenyl group optionally having substituent(s) (except for aphenyl group substituted only with halogen atom(s)), a 5-memberedaromatic heterocyclic group optionally having substituent(s), a6-membered aromatic heterocyclic group optionally having substituent(s),or a bicyclic aromatic heterocyclic group having 8 or 9 atoms andoptionally having substituent(s);

X is a group selected from the group consisting of the following a), b),and c),

a) an oxygen atom or a sulfur atom,

b) NR⁴, and

c) NOR⁴, wherein,

when X is b) or c), R⁴ is a hydrogen atom, a phenyl group optionallyhaving substituent(s), a heterocyclic group optionally havingsubstituent(s), or a C₁ to C₆ alkyl group optionally havingsubstituent(s);

R¹ is a hydrogen atom, a hydroxy group, a C₁ to C₆ alkoxy groupoptionally having substituent(s), or a C₁ to C₆ alkyl group optionallyhaving substituent(s);

R² and R³ are each independently a hydrogen atom or a C₁ to C₆ alkylgroup optionally having substituent(s) or together form a C₂ to C₆alkylene group; and

each carbon atom marked with an asterisk is an asymmetric carbon atom].

[2] The compound according to [1] or a pharmacologically acceptable saltthereof, wherein

in the formula (I), Ar² is a group selected from the group consisting ofthe following A1), A2), A3), A4), A5), A6), A7), A8), A9), and A10):

wherein, when Ar² is A2), W¹ is a nitrogen atom or CH optionallysubstituted with a hydrogen atom, with a halogen atom, or with a C₁ toC₆ alkyl group optionally having substituent(s);

when Ar² is A2), W² is CH or a nitrogen atom;

when Ar² is A3), A4), A5), or A6), W³ is an oxygen atom, a sulfur atom,or NH optionally substituted with a C₁ to C₆ alkyl group;

when Ar² is A3), A4), or A6), W⁴ is CH or a nitrogen atom;

when Ar² is A7), W⁵ is CH₂, an oxygen atom, or a sulfur atom;

when Ar² is A7), W⁶ is C═O, CH₂, CF₂, CHOH, NH optionally substitutedwith a C₁ to C₆ alkyl group, SO, SO₂, an oxygen atom, or a sulfur atom;

when Ar² is A8), W⁷ is NH optionally substituted with a C₁ to C₆ alkylgroup or C═O;

when Ar² is A8), W⁸ is C═O with W⁷ being NH optionally substituted witha C₁ to C₆ alkyl group and W⁸ is NH optionally substituted with a C₁ toC₆ alkyl group with W⁷ being C═O;

when Ar² is A10), W⁹ is a nitrogen atom or N═O;

when Ar² is A1), A2), A3), A4), or A5), R⁶ is a hydrogen atom, a halogenatom, a hydroxy group, a cyano group, a C₁ to C₆ alkyl group optionallyhaving substituent(s), a C₁ to C₆ alkoxy group optionally havingsubstituent(s), a C₁ to C₆ acyl group optionally having substituent(s),a C₁ to C₆ alkylsulfanyl group optionally having substituent(s), a C₁ toC₆ alkylsulfinyl group optionally having substituent(s), a C₁ to C₆alkylsulfonyl group optionally having substituent(s), a heterocyclicgroup optionally having substituent(s), —CONR¹⁰R¹¹, or —NR¹⁰R¹¹,wherein, when R⁶ is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁to C₆ alkyl group optionally having substituent(s), a C₁ to C₆ acylgroup optionally having substituent(s), or a C₁ to C₆ alkylsulfonylgroup optionally having substituent(s) and R¹¹ is a hydrogen atom or aC₁ to C₆ alkyl group optionally having substituent(s), or R¹⁰ and R¹¹together form a C₃ to C₁₀ heterocycloalkyl group;

when Ar² is A1), A2), A3), A4), A5), A6), A7), A8), A9), or A10), R⁷ isa hydrogen atom, a halogen atom, a C₁ to C₆ alkyl group optionallyhaving substituent(s), or a C₁ to C₆ alkoxy group optionally havingsubstituent(s);

when Ar² is A1), A7), A8), or A10), R⁸ is a hydrogen atom, a halogenatom, or a C₁ to C₆ alkyl group optionally having substituent(s);

when Ar² is A9), R⁹ is a hydrogen atom or a C₁ to C₆ alkyl group;

when Ar² is A7), m is 0 or 1; and

when Ar² is A8), n is 0 or 1;

provided that, when Ar² is A1), combinations of the substituents R⁶, R⁷and R⁸ exclude a combination of a hydrogen atom and a halogen atom.

[3] The compound according to [2] or a pharmacologically acceptable saltthereof, wherein

in the formula (I), Ar¹ is a group selected from the group consisting ofthe following B1), B2), B3), B4), B5), B6), B7), B8), B9), B10), B11),and B12):

wherein, when Ar¹ is B2), B3), B7), B8), B10), B11), or B12), R¹² is ahydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C₁ toC₆ alkyl group optionally having substituent(s), a C₁ to C₆ alkoxy groupoptionally having substituent(s), a C₃ to C₆ cycloalkyl group optionallyhaving substituent(s), a C₃ to C₆ cycloalkoxy group optionally havingsubstituent(s), a C₁ to C₆ acyl group optionally having substituent(s),a C₂ to C₆ alkenyl group optionally having substituent(s), a C₂ to C₆alkynyl group optionally having substituent(s), a C₁ to C₆alkoxycarbonyl group, a C₁ to C₆ alkylsulfanyl group optionally havingsubstituent(s), a C₁ to C₆ alkylsulfinyl group optionally havingsubstituent(s), a C₁ to C₆ alkylsulfonyl group optionally havingsubstituent(s), —CONR¹⁰R¹¹, —NR¹⁰R¹¹, an aryloxy group, or aheterocyclic group optionally having substituent(s), wherein, when R¹²is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁ to C₆ alkylgroup optionally having substituent(s), a C₁ to C₆ acyl group optionallyhaving substituent(s), or a C₁ to C₆ alkylsulfonyl group optionallyhaving substituent(s) and R¹¹ is a hydrogen atom or a C₁ to C₆ alkylgroup optionally having substituent(s), or R¹⁰ and R¹¹ together form aC₃ to C₁₀ heterocycloalkyl group;

when Ar¹ is B1), R¹² is a hydrogen atom, a halogen atom, a hydroxygroup, a cyano group, a C₁ to C₆ alkyl group optionally havingsubstituent(s), a C₁ to C₆ alkoxy group optionally havingsubstituent(s), a C₃ to C₆ cycloalkyl group optionally havingsubstituent(s), a C₃ to C₆ cycloalkoxy group optionally havingsubstituent(s), a C₁ to C₆ acyl group optionally having substituent(s),a C₂ to C₆ alkenyl group optionally having substituent(s), a C₂ to C₆alkynyl group optionally having substituent(s), a C₁ to C₆alkoxycarbonyl group, a C₁ to C₆ alkylsulfanyl group optionally havingsubstituent(s), a C₁ to C₆ alkylsulfinyl group optionally havingsubstituent(s), a C₁ to C₆ alkylsulfonyl group optionally havingsubstituent(s), —CONR¹⁰R¹¹, —NR¹⁰R¹¹, an aryloxy group, or aheterocyclic group optionally having substituent(s), wherein, when R¹²is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁ to C₆ alkylgroup optionally having substituent(s), a C₁ to C₆ acyl group optionallyhaving substituent(s), or a C₁ to C₆ alkylsulfonyl group optionallyhaving substituent(s) and R¹¹ is a hydrogen atom or a C₁ to C₆ alkylgroup optionally having substituent(s), or R¹⁰ and R¹¹ together form aC₃ to C₁₀ heterocycloalkyl group, and R¹³ is a hydrogen atom, a halogenatom, a hydroxy group, a cyano group, or a C₁ to C₆ alkyl group, or R¹²and R¹³ may together form a C₃ to C₅ alkylene group or a C₁ to C₂alkylenedioxy group;

when Ar¹ is B6), R¹³ is a hydrogen atom, a halogen atom, a hydroxygroup, a cyano group, or a C₁ to C₆ alkyl group;

when Ar¹ is B9), R¹⁴ and R¹⁵ are each independently a hydrogen atom, ahalogen atom, a cyano group, a C₁ to C₆ alkyl group, or a C₁ to C₆alkoxy group;

when Ar¹ is B2), one of W¹⁰ and W¹¹ is a nitrogen atom, and the otherthereof is CH or a nitrogen atom;

when Ar¹ is B6), B7), B8), B9), B10), B11), or B12), W¹² is an oxygenatom, a sulfur atom, or N—R¹⁶, wherein, when W¹² is an N—R¹⁶, R¹⁶ is ahydrogen atom or a C₁ to C₆ alkyl group; and

when Ar¹ is B6), B7), B8), or B9), W¹³ is CH or a nitrogen atom.

[4] The compound according to [3] or a pharmacologically acceptable saltthereof, wherein

when Ar² is A1), A2), A3), A4), or A5), R⁶ is a hydrogen atom, a halogenatom, a hydroxy group, a cyano group, a C₁ to C₆ alkyl group, a C₁ to C₆alkoxy group, a halo-C₁ to C₆ alkoxy group, a C₁ to C₆ acyl group, a C₁to C₆ alkylsulfanyl group, a C₁ to C₆ alkylsulfinyl group, a C₁ to C₆alkylsulfonyl group, a heterocyclic group optionally havingsubstituent(s), —CONR¹⁰R¹¹, or —NR¹⁰R¹¹, wherein, when R⁶ is —CONR¹⁰R¹¹or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆acyl group, or a C₁ to C₆ alkylsulfonyl group and R¹¹ is a hydrogen atomor a C₁ to C₆ alkyl group, or R¹⁰ and R¹¹ together form a C₃ to C₁₀heterocycloalkyl group;

when Ar² is A1), A2), A3), A4), A5), A6), A7), A8), A9), or A10), R⁷ isa hydrogen atom, a halogen atom, a C₁ to C₆ alkyl group, or a C₁ to C₆alkoxy group;

when Ar² is A1), A7), A8), or A10), R⁸ is a hydrogen atom, a halogenatom, or a C₁ to C₆ alkyl group; and

when Ar² is A9), R⁹ is a hydrogen atom or a C₁ to C₆ alkyl group;

provided that, when Ar² is A1), combinations of the substituents R⁶, R⁷and R⁸ exclude a combination of a hydrogen atom and a halogen atom.

[5] The compound according to [4] or a pharmacologically acceptable saltthereof, wherein

R¹ is a hydrogen atom, a hydroxy group, a C₁ to C₆ alkyl group, a C₁ toC₆ alkoxy group, a halo-C₁ to C₆ alkyl group, a hydroxy C₁ to C₆ alkylgroup, a carboxy C₁ to C₆ alkyl group, a carbamoyl C₁ to C₆ alkyl group,a mono C₁ to C₆ alkylcarbamoyl C₁ to C₆ alkyl group, a di-C₁ to C₆alkylcarbamoyl C₁ to C₆ alkyl group, an aminosulfonyl C₁ to C₆ alkylgroup, an aromatic heterocyclic C₁ to C₃ alkyl group optionally havingsubstituent(s), or a phenyl C₁ to C₃ alkyl group optionally havingsubstituent(s);

R² and R³ are each independently a hydrogen atom or a C₁ to C₃ alkylgroup or together form a C₂ to C₆ alkylene group;

when Ar¹ is B2), B3), B7), B8), B10), B11), or B12), R¹² is a hydrogenatom, a halogen atom, a hydroxy group, a cyano group, a C₁ to C₆ alkylgroup, a halo-C₁ to C₆ alkyl group, a hydroxy C₁ to C₆ alkyl group, a C₁to C₆ alkoxy group, a C₃ to C₆ cycloalkyl group, a C₃ to C₆ cycloalkoxygroup, a C₁ to C₆ acyl group, a C₂ to C₆ alkenyl group, a C₂ to C₆alkynyl group, a C₁ to C₆ alkoxycarbonyl group, a C₁ to C₆ alkylsulfanylgroup, a C₁ to C₆ alkylsulfinyl group, a C₁ to C₆ alkylsulfonyl group,—CONR¹⁰R¹¹, —NR¹⁰R¹¹, an aryloxy group, or a heterocyclic groupoptionally having substituent(s), wherein, when R¹² is —CONR¹⁰R¹¹ or—NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆acyl group, or a C₁ to C₆ alkylsulfonyl group and R¹¹ is a hydrogen atomor a C₁ to C₆ alkyl group, or R¹⁰ and R¹¹ together form a C₃ to C₁₀heterocycloalkyl group;

when Ar¹ is B1), R¹² is a hydrogen atom, a halogen atom, a hydroxygroup, a cyano group, a C₁ to C₆ alkyl group, a halo-C₁ to C₆ alkylgroup, a hydroxy C₁ to C₆ alkyl group, a C₁ to C₆ alkoxy group, a C₃ toC₆ cycloalkyl group, a C₃ to C₆ cycloalkoxy group, a C₁ to C₆ acylgroup, a C₂ to C₆ alkenyl group, a C₂ to C₆ alkynyl group, a C₁ to C₆alkoxycarbonyl group, a C₁ to C₆ alkylsulfanyl group, a C₁ to C₆alkylsulfinyl group, a C₁ to C₆ alkylsulfonyl group, —CONR¹⁰R¹¹,—NR¹⁰R¹¹, an aryloxy group, or a heterocyclic group optionally havingsubstituent(s), wherein, when R¹² is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is ahydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆ acyl group, or a C₁ toC₆ alkylsulfonyl group and R¹¹ is a hydrogen atom or a C₁ to C₆ alkylgroup, or R¹⁰ and R¹¹ together form a C₃ to C₁₀ heterocycloalkyl group,and R¹³ is a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, or a C₁ to C₆ alkyl group, or R¹² and R¹³ may together form a C₃to C₅ alkylene group or a C₁ to C₂ alkylenedioxy group; and

X is a group selected from the group consisting of the following a), b),and c),

a) an oxygen atom,

b) NR⁴, and

c) NOR⁴, wherein,

when X is b) or c), R⁴ is a hydrogen atom, a hydroxy C₁ to C₆ alkylgroup, a phenyl group, a heterocyclic group, or a C₁ to C₆ alkyl group.[6] The compound according to [5] or a pharmacologically acceptable saltthereof, wherein

in the formula (I), Ar² is a group selected from the group consisting ofA1), A2a), A3), and A7a):

wherein, when Ar² is A2a), W² is the same as that defined in [2] whenAr² is A2);

when Ar² is A3), W⁴ is the same as that defined in [2] when Ar² is A3);

when Ar² is A7a), W⁶ is the same as that defined in [2] when Ar² is A7);

when Ar² is A1), A2a), A3), or A7a), R⁷ is the same as that defined in[4] when Ar² is A1), A2), A3), or A7);

when Ar² is A1) or A7a), R⁸ is the same as that defined in [4] when Ar²is A1) or A7);

when Ar² is A7a), m is the same as that defined in [2] when Ar² is A7);

when Ar² is A1), A2a), or A3), R⁶ is a hydrogen atom, a halogen atom, acyano group, a C₁ to C₆ alkyl group, a C₁ to C₆ alkoxy group, a halo-C₁to C₆ alkoxy group, a C₁ to C₆ acyl group, a C₁ to C₆ alkylsulfanylgroup, a C₁ to C₆ alkylsulfinyl group, —CONR¹⁰R¹¹, or —NR¹⁰R¹¹, wherein,when R⁶ is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁ to C₆alkyl group, or a C₁ to C₆ acyl group and R¹¹ is a hydrogen atom or a C₁to C₆ alkyl group, or R¹⁰ and R¹¹ may together form a pyrrolidinylgroup, a piperidinyl group, a piperazinyl group, or a morpholinyl group;and

when Ar² is A3), W³ is an oxygen atom or a sulfur atom;

provided that, when Ar² is A1), combinations of the substituents R⁶, R⁷and R⁸ exclude a combination of a hydrogen atom and a halogen atom.

[7] The compound according to [6] or a pharmacologically acceptable saltthereof, wherein

in the formula (I), Ar¹ is a group selected from the group consisting ofB1), B2), B6a), B9a), and B9b):

wherein, when Ar¹ is B6a), R¹³ is the same as that defined in [3] whenAr¹ is B6);

when Ar¹ is B9a) or B9b), R¹⁴ and R¹⁵ are the same as those defined in[3] when Ar¹ is B9);

when Ar¹ is B2), W¹⁰ and W¹¹ are the same as those defined in [3] whenAr¹ is B2);

when Ar¹ is B2), R¹² is a hydrogen atom, a halogen atom, a hydroxygroup, a cyano group, a C₁ to C₆ alkyl group, a halo-C₁ to C₆ alkylgroup, a hydroxy C₁ to C₆ alkyl group, a C₁ to C₆ alkoxy group, a C₃ toC₆ cycloalkyl group, a C₃ to C₆ cycloalkoxy group, a C₁ to C₆ acylgroup, a C₂ to C₆ alkenyl group, a C₁ to C₆ alkoxycarbonyl group, a C₁to C₆ alkylsulfanyl group, a C₁ to C₆ alkylsulfinyl group, a C₁ to C₆alkylsulfonyl group, —CONR¹⁰R¹¹, —NR¹⁰R¹¹, an aryloxy group, or aheterocyclic group optionally having substituent(s), wherein, when R¹²is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁ to C₆ alkylgroup, or a C₁ to C₆ acyl group and R¹¹ is a hydrogen atom or a C₁ to C₆alkyl group, or R¹⁰ and R¹¹ may together form a pyrrolidinyl group, apiperidinyl group, a piperazinyl group, or a morpholinyl group;

when Ar¹ is B1), R¹² is a hydrogen atom, a halogen atom, a hydroxygroup, a cyano group, a C₁ to C₆ alkyl group, a halo-C₁ to C₆ alkylgroup, a hydroxy C₁ to C₆ alkyl group, a C₁ to C₆ alkoxy group, a C₃ toC₆ cycloalkyl group, a C₃ to C₆ cycloalkoxy group, a C₁ to C₆ acylgroup, a C₂ to C₆ alkenyl group, a C₁ to C₆ alkoxycarbonyl group, a C₁to C₆ alkylsulfanyl group, a C₁ to C₆ alkylsulfinyl group, a C₁ to C₆alkylsulfonyl group, —CONR¹⁰R¹¹, —NR¹⁰R¹¹, an aryloxy group, or aheterocyclic group optionally having substituent(s), wherein, when R¹²is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, a C₁ to C₆ alkylgroup, or a C₁ to C₆ acyl group and R¹¹ is a hydrogen atom or a C₁ to C₆alkyl group, or R¹⁰ and R¹¹ may together form a pyrrolidinyl group, apiperidinyl group, a piperazinyl group, or a morpholinyl group, and R¹³is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, or aC₁ to C₆ alkyl group, or R¹² and R¹³ may together form a C₃ to C₅alkylene group or a C₁ to C₂ alkylenedioxy group; and

when Ar¹ is B6a), B9a), or B9b), W¹² is an oxygen atom or a sulfur atom.

[8] The compound according to [7] or a pharmacologically acceptable saltthereof, wherein

in the formula (I), Ar² is a group selected from the group consisting ofA1a), A2b), A3a), and A7b):

wherein, when Ar² is A1a), R⁶ is the same as that defined in [6] whenAr² is A1);

when Ar² is A1a) or A7b), R⁸ is the same as that defined in [4] when Ar²is A1) or A7);

when Ar² is A7b), m is the same as that defined in [2] when Ar² is A7);

R¹ is a hydrogen atom, a hydroxy group, a C₁ to C₃ alkyl group, a C₁ toC₃ alkoxy group, a hydroxy C₁ to C₄ alkyl group, a carboxy C, to C₃alkyl group, a carbamoyl C₁ to C₃ alkyl group, a mono-C₁ to C₂alkylcarbamoyl C₁ to C₃ alkyl group, or a di-C₁ to C₂ alkylcarbamoyl C₁to C₃ alkyl group;

R² and R³ are each independently a hydrogen atom or a C₁ to C₃ alkylgroup;

when X is b) or c), R⁴ is a hydrogen atom, a hydroxy C₁ to C₄ alkylgroup, or a C₁ to C₃ alkyl group;

when Ar² is A2b) or A3a), R^(6a) is a C₁ to C₃ alkoxy group;

when Ar² is A1a), A2b), A3a), or A7b), R⁷ is a hydrogen atom, a fluorineatom, a chlorine atom, or a C₁ to C₃ alkyl group; and

when Ar² is A7b), W⁶ is C═O, CH₂, CF₂, CHOH, or an oxygen atom;

provided that, when Ar¹ is A1a), combinations of the substituents R⁶, R⁷and R⁸ exclude a combination of a hydrogen atom and a halogen atom.

[9] The compound according to [8] or a pharmacologically acceptable saltthereof, wherein

in the formula (I), Ar² is a group selected from the group consisting ofA1a), A2b), and A7c):

wherein, when Ar² is A2b), R^(6a) is the same as that defined in [8]when Ar² is A2b);

when Ar² is A1a) or A7c), R⁸ is the same as that defined in [4] when Ar²is A1) or A7);

when Ar² is A7c), m is the same as that defined in [8] when Ar² is A7b);

when Ar² is A1a), R⁶ is a hydrogen atom, a fluorine atom, a chlorineatom, a cyano group, a C₁ to C₆ alkyl group, a C₁ to C₆ alkoxy group, ahalo-C₁ to C₆ alkoxy group, a C₁ to C₆ alkylsulfanyl group, a C₁ to C₆alkylsulfinyl group, or —CONR¹⁰R¹¹, wherein, when R⁶ is —CONR¹⁰R¹¹, R¹⁰is a hydrogen atom, a C₁ to C₆ alkyl group, or a C₁ to C₆ acyl group andR¹¹ is a hydrogen atom or a C₁ to C₆ alkyl group, or R¹⁰ and R¹¹ maytogether form a pyrrolidinyl group, a piperidinyl group, a piperazinylgroup, or a morpholinyl group; and

when Ar² is A1a), A2b), or A7c), R⁷ is a hydrogen atom, a fluorine atom,or a chlorine atom;

provided that, when Ar² is A1a), combinations of the substituents R⁶, R⁷and R⁸ exclude a combination of a hydrogen atom and a halogen atom.

[10] The compound according to [9] or a pharmacologically acceptablesalt thereof, wherein

in the formula (I), Ar¹ is a group selected from the group consisting ofB1), B2), B6b), B9c), and B9d):

wherein R¹ is a hydrogen atom, a hydroxy group, a C₁ to C₃ alkyl group,a C₁ to C₃ alkoxy group, or a hydroxy C₁ to C₄ alkyl group;

when Ar¹ is B1) or B2), R¹² is a hydrogen atom, a fluorine atom, achlorine atom, a cyano group, a C₁ to C₃ alkyl group, or a C₁ to C₆alkoxy group;

when Ar¹ is B1) or B6b), R¹³ is a hydrogen atom, a hydroxy group, afluorine atom, or a chlorine atom;

when Ar¹ is B9c) or B9d), R¹⁴ is a hydrogen atom, a fluorine atom, achlorine atom, a C₁ to C₃ alkyl group, a methoxy group, or an ethoxygroup;

when Ar¹ is B9c) or B9d), R¹⁵ is a hydrogen atom, a fluorine atom, or achlorine atom; and

when Ar¹ is B2), one of W¹⁰ and W¹¹ is N, and the other thereof is CH.

11] The compound according to [10] or a pharmacologically acceptablesalt thereof, wherein

in the formula (I), Ar¹ is a group selected from the group consisting ofB1), B6b), and B9c1):

wherein when Ar¹ is B1), R¹² is the same as that defined in [10] whenAr¹ is B1);

when Ar¹ is B1) or B6b), R¹³ is the same as that defined in [10] whenAr¹ is B1) or B6b); and

when Ar¹ is B9c1), R¹⁴ is the same as that defined in [10] when Ar¹ isB9c).

[12] The compound according to [11] or a pharmacologically acceptablesalt thereof, wherein

in the formula (I), Ar² is a group selected from the group consisting ofA1b), A2b), and A7c):

wherein, when Ar² is A2b), R^(6a) is the same as that defined in [8]when Ar² is A2b);

when Ar² is A7c), m is the same as that defined in [8] when Ar² is A7b);

when Ar² is A1b), R⁶ is a cyano group, an ethyl group, or a C₁ to C₃alkoxy group;

R⁷ is a fluorine atom or a chlorine atom; and

when Ar² is A1b) or A7c), R⁸ is a hydrogen atom, a fluorine atom, achlorine atom, or a C₁ to C₃ alkyl group.

[13] The compound according to [1] or a pharmacologically acceptablesalt thereof, wherein

the compound represented by the formula (1) is

-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(3,4-difluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*)-4-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   1-[(3S*,4R*)-4-(2-chloro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxy-2-methylphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(2,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(3,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(3-fluoro-5-methoxypyridin-2-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(5-methoxythiophen-2-yl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylthiophenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-methoxyphenyl)urea,-   (−)-1-(5-chlorothiazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(5-chloropyridin-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(benzo[b]thiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(5-methylthiophen-2-yl)urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,5S*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,5R*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea,-   (+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-2-oxo-4-phenylpyrrolidin-3-yl]urea,-   (±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea,-   (±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(trifluoromethoxy)phenyl]urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-phenoxyphenyl)urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3,4-difluorophenyl)urea,-   (−)-1-(5-chlorothiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(p-tolyl)urea,-   (−)-1-[(3S*,4R*)-1-ethyl-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-1-(1-hydroxy-2-methylpro    pan-2-yl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (±)-trans-1-(4-chlorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (+)-trans-1-(4-chlorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-trans-1-(4-chlorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylacetamide,-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic    acid (isomer A),-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylpropionamide    (isomer A),-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic    acid (isomer B),-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylpropionamide    (isomer B),-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N,2-dimethylpropionamide,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (+)-1-(4-fluorophenyl)-3-[(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-3,5-difluoro-4-{3R*,4S*)-4-[3-(4-fluorophenylureido]-5-oxopyrrolidin-3-yl}benzamide,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*,Z)-4-(2-fluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-(4-fluorophenyl)-3-{(3S*,4R*,Z)-2-[(2-hydroxyethoxy)imino]-4-(4-methoxyphenyl)pyrrolidin-3-yl}urea,-   (−)-1-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}-3-(4-fluorophenyl)urea,-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methylimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea,-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(2-hydroxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-hydroxy-4-methylphenyl)urea,-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluoro-3-hydroxyphenyl)urea,-   (−)-1-(4-chloro-3-hydroxyphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]urea,-   (−)-1-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}-3-(p-tolyl)urea,    or-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-phenylurea.    [14] A pharmaceutical containing, as an active ingredient, the    compound according to any one of [1] to [13] or a pharmacologically    acceptable salt thereof.    [15] An FPRL1 agonist containing, as an active ingredient, the    compound according to any one of [1] to [13] or a pharmacologically    acceptable salt thereof.    [16] A method of treatment or prevention of inflammatory diseases,    chronic airway diseases, cancers, septicemia, allergic symptoms, HIV    retrovirus infection, circulatory disorders, neuroinflammation,    nervous disorders, pains, prion diseases, amyloidosis, and immune    disorders, comprising administering the compound according to any    one of [1] to [13] or a pharmacologically acceptable salt thereof.    [17] Use of the compound according to any one of [1] to [13] or a    pharmacologically acceptable salt thereof to produce a    pharmaceutical for treatment or prevention of inflammatory diseases,    chronic airway diseases, cancers, septicemia, allergic symptoms, HIV    retrovirus infection, circulatory disorders, neuroinflammation,    nervous disorders, pains, prion diseases, amyloidosis, and immune    disorders.    [18] A pharmaceutical composition containing the compound according    to any one of [1] to [13] or a pharmacologically acceptable salt    thereof and a pharmaceutically acceptable carrier, used for    prevention or treatment of inflammatory diseases, chronic airway    diseases, cancers, septicemia, allergic symptoms, HIV retrovirus    infection, circulatory disorders, neuroinflammation, nervous    disorders, pains, prion diseases, amyloidosis, and immune disorders.

Advantageous Effects of Invention

The compound (I) or a pharmacologically acceptable salt thereofexhibited superior agonist activity in, for example, a test of calciuminflux into FPRL1-overexpressing cells. The compound (I) and saltsthereof strongly suppressed lipopolysaccharide-induced neutrophilicinfiltration into the lungs of mice. In addition, the compound (I) andsalts thereof have low toxicity and are therefore safe. Therefore, thecompound (I) according to the present invention or a pharmacologicallyacceptable salt thereof is useful as a therapeutic or prophylactic agentfor inflammatory diseases, chronic airway diseases, cancers, septicemia,allergic symptoms, HIV retrovirus infection, circulatory disorders,neuroinflammation, nervous disorders, pains, prion diseases,amyloidosis, immune disorders and the like.

In addition, the compound (I) according to the present invention or apharmacologically acceptable salt thereof is highly useful fortreatment, prevention, or suppression of various disease statesassociated with the FPRL1 receptor (such as Behcet's disease, Sweetdisease, systemic lupus erythematosus (SLE), Wegener's granulomatosis,virus infection, diabetes, amputations, cancers, bacterial infection,physical external injuries, physical disorders including exposure toradiation, vasoconstriction, anaphylactic reactions, allergic reactions,rhinitis, shocks (endotoxic, hemorrhagic, traumatic, splanchnicischemia, and circulatory shocks), rheumatoid arthritis, gout,psoriasis, benign prostatic hyperplasia, myocardial ischemia, myocardialinfarction, brain injuries, pulmonary diseases, COPD, COAD, COLD, acutelung injury, acute respiratory distress syndrome, chronic bronchitis,pulmonary emphysema, asthma (allergic asthma and non-allergic asthma),cystic pulmonary fibrosis, nephropathy, renal glomerular diseases,ulcerative colitis, IBD, Crohn's disease, periodontitis, pains,Alzheimer's disease, AIDS, uveitic glaucoma, conjunctivitis, Sjoegren'ssyndrome, and rhinitis).

DESCRIPTION OF EMBODIMENTS

Terms in the present description will be described.

The term “halogen atom” as used herein means a fluorine atom, a chlorineatom, a bromine atom, or an iodine atom. Preferably, the halogen atom isa fluorine atom or a chlorine atom.

The 5-membered aromatic heterocyclic group in the term “5-memberedaromatic heterocyclic group optionally having substituent(s)” as usedherein means a 5-membered aromatic heterocyclic group containing, in itsring, 1 to 4 atoms selected from sulfur, oxygen, and nitrogen atoms.Examples of the 5-membered aromatic heterocyclic group may include afuryl group, a thienyl group, a pyrrolyl group, an azepinyl group, apyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolylgroup, a thiazolyl group, an isothiazolyl group, a 1,2,3-oxadiazolylgroup, a triazolyl group, a tetrazolyl group, a thiadiazolyl group andthe like.

The 6-membered aromatic heterocyclic group in the term “6-memberedaromatic heterocyclic group optionally having substituent(s)” as usedherein means a 6-membered aromatic heterocyclic group containing, in itsring, 1 to 4 nitrogen atoms. Examples of the 6-membered aromaticheterocyclic group may include a pyridyl group, a pyridazinyl group, apyrimidinyl group, a pyrazinyl group and the like.

The bicyclic aromatic heterocyclic group having 8 or 9 atoms in the term“bicyclic aromatic heterocyclic group having 8 or 9 atoms and optionallyhaving substituent(s)” as used herein means a bicyclic aromaticheterocyclic group having 8 or 9 atoms containing 1 to 4 atoms selectedfrom sulfur, oxygen, and nitrogen atoms. Examples of the bicyclicaromatic heterocyclic group having 8 or 9 atoms may include abenzofuranyl group, an isobenzofuranyl group, a benzoxazolyl group, abenzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group,a benzimidazolyl group, a benzothiophenyl group, an indolyl group, anisoindolyl group, an indazolyl group, a thiazolopyridyl group, anoxazolopyrazinyl group and the like.

The C₁ to C₆ alkoxy group in the terms “C₁ to C₆ alkoxy group optionallyhaving substituent(s)” and “C₁ to C₆ alkoxy group” as used herein meansa linear or branched alkoxy group having 1 to 6 carbon atoms. Examplesof the C₁ to C₆ alkoxy group may include a methoxy group, an ethoxygroup, a propoxy group, an isopropoxy group, an isobutoxy group, abutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxygroup, a hexyloxy group and the like. Preferred examples may include amethoxy group and an ethoxy group.

The C₁ to C₆ alkyl group in the terms “C₁ to C₆ alkyl group optionallyhaving substituent(s)” and “C₁ to C₆ alkyl group” as used herein means alinear or branched alkyl group having 1 to 6 carbon atoms and optionallyhaving substituent(s). Examples of the C₁ to C₆ alkyl group may includea methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a 1-methylbutylgroup, a 2-methyl butyl group, a 1,2-dimethylpropyl group, a hexylgroup, an isohexyl group and the like.

The C₁ to C₆ acyl group in the terms “C₁ to C₆ acyl group optionallyhaving substituent(s)” and “C₁ to C₆ acyl group” as used herein means anacyl group derived from a linear or branched aliphatic carboxylic acidhaving 1 to 6 carbon atoms. Examples of the C₁ to C₆ acyl group mayinclude a formyl group, an acetyl group, a propanoyl group, a butanoylgroup, a pentanoyl group, a hexanoyl group and the like.

The C₁ to C₆ alkylsulfanyl group in the terms “C₁ to C₆ alkylsulfanylgroup optionally having substituent(s)” and “C₁ to C₆ alkylsulfanylgroup” as used herein means a linear or branched alkylsulfanyl grouphaving 1 to 6 carbon atoms or a cyclic alkylsulfanyl group having 3 to 6carbon atoms. Examples of the C₁ to C₆ alkylsulfanyl group may include amethylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, anisopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanylgroup, a sec-butylsulfanyl group, a tert-butylsulfanyl group, acyclopropylsulfanyl group, a cyclobutylsulfanyl group, acyclopentylsulfanyl group and the like.

The C₁ to C₆ alkylsulfinyl group in the terms “C₁ to C₆ alkylsulfinylgroup optionally having substituent(s)” and “C₁ to C₆ alkylsulfinylgroup” as used herein means a linear or branched alkylsulfinyl grouphaving 1 to 6 carbon atoms or a cyclic alkylsulfinyl group having 3 to 6carbon atoms. Examples of the C₁ to C₆ alkylsulfinyl group may include amethylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, anisopropylsulfinyl group, a butylsulfinyl group, an isobutylsulfinylgroup, a sec-butylsulfinyl group, a tert-butylsulfinyl group, acyclopropylsulfinyl group, a cyclobutylsulfinyl group, acyclopentylsulfinyl group and the like.

The C₁ to C₆ alkylsulfonyl group in the terms “C₁ to C₆ alkylsulfonylgroup optionally having substituent(s)” and “C₁ to C₆ alkylsulfonylgroup” as used herein means a linear or branched alkylsulfonyl grouphaving 1 to 6 carbon atoms or a cyclic alkylsulfonyl group having 3 to 6carbon atoms. Examples of the C₁ to C₆ alkylsulfonyl group may include amethylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, anisopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonylgroup, a sec-butylsulfonyl group, a tert-butylsulfonyl group, acyclopropylsulfonyl group, a cyclobutylsulfonyl group, acyclopentylsulfonyl group and the like.

The heterocyclic group in the term “heterocyclic group optionally havingsubstituent(s)” as used herein means a 5- to 7-membered heterocyclicgroup containing 1 to 4 atoms selected from sulfur, oxygen, and nitrogenatoms. Examples of the heterocyclic group may include: aromaticheterocyclic groups such as a furyl group, a thienyl group, a pyrrolylgroup, an azepinyl group, a pyrazolyl group, an imidazolyl group, anoxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolylgroup, a 1,2,3-oxadiazolyl group, a triazolyl group, a tetrazolyl group,a thiadiazolyl group, a pyranyl group, a pyridyl group, a pyridazinylgroup, a pyrimidinyl group, and a pyrazinyl group; unsaturatedheterocyclic groups such as a pyrrolinyl group, an imidazolinyl group, apyrazolinyl group, a dihydropyranyl group, a dihydrothiopyranyl group,and a dihydropyridyl group; and saturated heterocyclic groups such as amorpholinyl group, a thiomorpholinyl group, a pyrrolidinyl group, animidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, apyrazolinyl group, a piperidinyl group, a piperazinyl group, atetrahydrofuranyl group and the like.

The above “heterocyclic group” may be annelated with another cyclicgroup. Examples of the heterocyclic group annelated with another cyclicgroup may include an isobenzofuranyl group, a benzoxazolyl group, abenzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group,a chromenyl group, a chromanonyl group, a xanthenyl group, aphenoxathiinyl group, an indolizinyl group, an isoindolizinyl group, anindolyl group, an indazolyl group, a purinyl group, a quinolizinylgroup, an isoquinolyl group, a quinolyl group, a phthalazinyl group, anaphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, acarbazolyl group, a carbolinyl group, an acridinyl group, anisoindolinyl group and the like.

The term “C₃ to C₁₀ heterocycloalkyl group” as used herein means amonocyclic, bicyclic, or tricyclic non-aromatic heterocycloalkyl groupwhich has a ring structure containing at least one nitrogen atom andoptionally containing an oxygen atom or a sulfur atom and in which thenumber of carbon atoms forming the ring(s) of the cyclic group is 4 to10. Examples of the C₃ to C₁₀ heterocycloalkyl group may include anazetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazylgroup, a morpholyl group and the like.

The C₃ to C₆ cycloalkyl group in the terms “C₃ to C₆ cycloalkyl groupoptionally having substituent(s)” and “C₃ to C₆ cycloalkyl group” asused herein means a monocyclic saturated alicyclic hydrocarbon grouphaving 3 to 6 carbon atoms. Examples of the C₃ to C₆ cycloalkyl groupmay include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group and the like.

The C₃ to C₆ cycloalkoxy group in the terms “C₃ to C₆ cycloalkoxy groupoptionally having substituent(s)” and “C₃ to C₆ cycloalkoxy group” asused herein means a cyclic alkoxy group having 3 to 6 carbon atoms.Examples of the C₃ to C₆ cycloalkoxy group may include a cyclopropyloxygroup, a cyclobutyloxy group, a cyclopentyloxy group, and acyclohexyloxy group.

The C₂ to C₆ alkenyl group in the terms “C₂ to C₆ alkenyl groupoptionally having substituent(s)” and “C₂ to C₆ alkenyl group” as usedherein means a linear or branched unsaturated hydrocarbon group having 2to 6 carbon atoms and having at least one double bond. Examples of theC₂ to C₆ alkenyl group may include a vinyl group, a 2-propenyl group, a1-propenyl group, a 3-propenyl group, a 1-buten-1-yl group, a1-buten-2-yl group, a 1-buten-3-yl group, a 1-buten-4-yl group, a2-buten-1-yl group, a 2-buten-2-yl group, a 1-penten-1-yl group, a1-penten-2-yl group, a 1-penten-3-yl group, a 2-penten-1-yl group, a2-penten-2-yl group, a 2-penten-3-yl group, a 1-hexen-1-yl group, a1-hexen-2-yl group, a 1-hexen-3-yl group, a 2-methyl-1-propen-1-yl groupand the like.

The “C₂ to C₆ alkynyl group” in the term “C₂ to C₆ alkynyl groupoptionally having substituent(s)” as used herein means a linear orbranched unsaturated hydrocarbon group having 2 to 6 carbon atoms andhaving at least one triple bond. Examples of the C₂ to C₆ alkynyl groupmay include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a1-butynyl group, a 2-butynyl group, a 3-butynyl group, a3-methyl-1-propynyl group, a 1-ethynyl-2-propynyl group, a2-methyl-3-propynyl group, a 1-pentynyl group, a 1-hexynyl group, a1,3-hexanediynyl group, a 1,5-hexanediynyl group and the like.

The C₁ to C₆ alkoxycarbonyl group in the terms “C₁ to C₆ alkoxycarbonylgroup optionally having substituent(s)” and “C₁ to C₆ alkoxycarbonylgroup” as used herein means a linear or branched alkoxycarbonyl grouphaving 1 to 6 carbon atoms. Examples of the C₁ to C₆ alkoxycarbonylgroup may include a methoxycarbonyl group, an ethoxycarbonyl group, apropoxycarbonyl group, an isopropoxycarbonyl group, an isobutoxycarbonylgroup, a butoxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonylgroup and the like. Preferred examples thereof may include amethoxycarbonyl group and a tert-butoxycarbonyl group.

The term “halo-C₁ to C₆ alkoxy group” as used herein means a C₁ to C₆alkoxy group substituted with 1 to 5 halogen atoms of the same type ordifferent types. Examples of the halo-C₁ to C₆ alkoxy group may includea fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxygroup,a 2-fluoroethoxygroup, a 2-chloroethoxygroup, a 2,2-difluoroethoxygroup, a 1,1-difluoroethoxy group, a 1,2-difluoroethoxy group, a2,2,2-trifluoroethoxy group, a 1,1,2,2,2-pentafluoroethoxy group, a2,2,2-trichloroethoxy group, a 3-fluoropropoxy group, a 2-fluoropropoxygroup, a 1-fluoropropoxy group, a 3,3-difluoropropoxy group, a2,2-difluoropropoxy group, a 1,1-difluoropropoxy group, a 4-fluorobutoxygroup, a 5-fluoropentoxy group, a 6-fluorohexyloxy group and the like.

The term “hydroxy C₁ to C₆ alkyl group” as used herein means a C₁ to C₆alkyl group substituted with a hydroxy group. Examples of the hydroxy C₁to C₆ alkyl group may include a 2-hydroxyethyl group, a 1-hydroxyethylgroup, a 3-hydroxypropyl group, a 2-hydroxypropyl group, a1-hydroxypropyl group, a 4-hydroxybutyl group, a 3-hydroxybutyl group, a2-hydroxybutyl group, a 1-hydroxybutyl group, a 5-hydroxypentyl group, a6-hydroxyhexyl group and the like.

Examples of the “C₁ to C₂ alkylenedioxy group” as used herein mayinclude a methylenedioxy group (—O—CH₂—O—) and an ethylenedioxy group(—O—CH₂CH₂—O—).

The term “C₂ to C₆ alkylene group” as used herein means a divalentlinear or branched saturated hydrocarbon chain having 2 to 6 carbonatoms. Examples of the C₂ to C₆ alkylene group may include —(CH₂)₂—,—(CH₂)₃—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —(CH₂)₄—, —CH(CH₃)—(CH₂)₂—,—(CH₂)₂—CH(CH₃)—, —CH(CH₂CH₃)—CH₂—, —C(CH₃)₂CH₂—, —CH₂—C(CH₃)₂—,—CH(CH₃)—CH(CH₃)—, —(CH₂)₅—, —CH(CH₃)—(CH₂)₃—, —C(CH₃)₂CH₂CH₂—,—(CH₂)₆—, —C(CH₃)₂—(CH₂)₃— and the like. Preferred examples thereof mayinclude —(CH₂)₂— and —(CH₂)₃—.

The term “C₃ to C₅ alkylene group” as used herein means a divalentlinear or branched saturated hydrocarbon chain having 3 to 5 carbonatoms. Examples of the C₃ to C₅ alkylene group may include —(CH₂)₃—,—CH(CH₃) CH₂—, —CH₂CH(CH₃)—, —(CH₂)₄—, —CH(CH₃)—(CH₂)₂—,—(CH₂)₂—CH(CH₃)—, —CH(CH₂CH₃)—CH₂—, —C(CH₃)₂CH₂—, —CH₂—C(CH₃)₂—,—CH(CH₃)—CH(CH₃)—, —(CH₂)₅—, —CH(CH₃)—(CH₂)₃—, —C(CH₃)₂CH₂CH₂— and thelike.

The term “aryloxy group” as used herein means an aromatic hydrocarbonalkoxy group having 6 to 14 carbon atoms. Examples of the aryloxy groupmay include a phenyloxy group, an indenyloxy group, a naphthyloxy group,a phenanthrenyloxy group, an anthracenyloxy group and the like.

The term “carboxy C₁ to C₆ alkyl group” as used herein means a C₁ to C₆alkyl group substituted with a carboxylic acid. Examples of the carboxyC₁ to C₆ alkyl group may include a carboxymethyl group, a 2-carboxyethylgroup, a 2-carboxypropyl group, a 3-carboxypropyl group, a4-carboxybutyl group, a 5-carboxypentyl group, a 6-carboxyhexyl groupand the like.

The term “carbamoyl C₁ to C₆ alkyl group” as used herein means a C₁ toC₆ alkyl group substituted with a carbamoyl group. Examples of thecarbamoyl C₁ to C₆ alkyl group may include a carbamoylmethyl group, a2-carbamoylethyl group, a 2-carbamoylpropyl group, a 3-carbamoylpropylgroup, a 4-carbamoylbutyl group, a 5-carbamoylpentyl group, a6-carbamoylhexyl group and the like.

The term “mono C₁ to C₆ alkylcarbamoyl C₁ to C₆ alkyl group” as usedherein means a C₁ to C₆ alkyl group substituted with a carbamoyl groupin which one hydrogen atom in the amino group is substituted with a C₁to C₆ alkyl group. Examples of the mono C₁ to C₆ alkylcarbamoyl C₁ to C₆alkyl group may include an N-methylcarbamoylmethyl group, anN-ethylcarbamoylmethyl group, a 2-(N-methylcarbamoyl)ethyl group, a2-(N-ethylcarbamoyl)ethyl group, a 2-(N-propylcarbamoyl)ethyl group, a3-(N-methylcarbamoyl)propyl group, a 4-(N-ethylcarbamoyl)butyl group, a5-(N-ethylcarbamoyl)pentyl group, a 6-(N-propylcarbamoyl)hexyl group andthe like.

The term “di-C₁ to C₆ alkylcarbamoyl C₁ to C₆ alkyl group” as usedherein means a C₁ to C₆ alkyl group substituted with a carbamoyl groupin which two hydrogen atoms in the amino group are substituted with C₁to C₆ alkyl groups. Examples of the di-C₁ to C₆ alkylcarbamoyl C₁ to C₆alkyl group may include an N,N-dimethylcarbamoylmethyl group, anN-ethyl-N-methylcarbamoylmethyl group, a 2-(N,N-dimethylcarbamoyl)ethylgroup, a 2-(N-ethyl-N-methylcarbamoyl)ethyl group, a2-(N-methyl-N-propylcarbamoyl)ethyl group, a3-(N,N-dimethylcarbamoyl)propyl group, a 4-(N,N-diethylcarbamoyl)butylgroup, a 5-(N-ethyl-N-propylcarbamoyl)pentyl group, a6-(N,N-dipropylcarbamoyl)hexyl group and the like.

The term “C₁ to C₆ alkylamino group” as used herein means an amino groupin which one or two hydrogen atoms in the amino group are substitutedwith linear or branched alkyl groups having 1 to 6 carbon atoms.Examples of the C₁ to C₆ alkylamino group may include a methylaminogroup, an ethylamino group, a propylamino group, an isopropylaminogroup, a butylamino group, an isobutylamino group, a sec-butylaminogroup, a tert-butylamino group, a pentylamino group, an isopentylaminogroup, a neopentylamino group, a 1-methylbutylamino group, a2-methylbutylamino group, a 1,2-dimethylpropylamino group, a hexylaminogroup, an isohexylamino group, a dimethylamino group, a diethylaminogroup, an N-ethyl-N-methylamino group, an N-ethyl-N-propylamino groupand the like.

The term “C₁ to C₆ acylamino group” as used herein means an amino groupsubstituted with C₁ to C₆ acyl. Examples of the C₁ to C₆ acylamino groupmay include a formylamino group, an acetylamino group, a propanoylaminogroup, a butanoylamino group, a pentanoylamino group, a hexanoylaminogroup and the like.

The term “C₁ to C₃ alkyl group” as used herein means a linear orbranched alkyl group having 1 to 3 carbon atoms. Examples of the C₁ toC₃ alkyl group may include a methyl group, an ethyl group, a propylgroup, and an isopropyl group.

The term “C₁ to C₃ alkoxy group” as used herein means a linear orbranched alkoxy group having 1 to 3 carbon atoms. Examples of the C₁ toC₃ alkoxy group may include a methoxy group, an ethoxy group, a propoxygroup, and an isopropoxy group.

The term “hydroxy C₁ to C₄ alkyl group” as used herein means a linear orbranched alkyl group having 1 to 4 carbon atoms and substituted with ahydroxy group. Examples of the hydroxy C₁ to C₄ alkyl group may includea 2-hydroxyethyl group, a 1-hydroxyethyl group, a 3-hydroxypropyl group,a 2-hydroxypropyl group, a 1-hydroxypropyl group, a 4-hydroxybutylgroup, a 3-hydroxybutyl group and the like.

The term “carboxy C₁ to C₃ alkyl group” as used herein means a C₁ to C₃alkyl group substituted with a carboxylic acid. Examples of the carboxyC₁ to C₃ alkyl group may include a carboxymethyl group, a 2-carboxyethylgroup, a 2-carboxypropyl group, a 3-carboxypropyl group and the like.

The term “carbamoyl C₁ to C₃ alkyl group” as used herein means a C₁ toC₃ alkyl group substituted with a carbamoyl group. Examples of thecarbamoyl C₁ to C₃ alkyl group may include a carbamoylmethyl group, a2-carbamoylethyl group, a 2-carbamoylpropyl group, a 3-carbamoylpropylgroup and the like.

The term “mono C₁ to C₂ alkylcarbamoyl C₁ to C₃ alkyl group” as usedherein means a C₁ to C₃ alkyl group substituted with a carbamoyl groupin which one hydrogen atom in the amino group is substituted with a C₁to C₂ alkyl group. Examples of the mono C₁ to C₂ alkylcarbamoyl C₁ to C₃alkyl group may include an N-methylcarbamoylmethyl group, anN-ethylcarbamoylmethyl group, a 2-(N-methylcarbamoyl)ethyl group, a2-(N-ethylcarbamoyl)ethyl group, a 3-(N-methylcarbamoyl)propyl group andthe like.

The term “di-C₁ to C₂ alkylcarbamoyl C₁ to C₃ alkyl group” as usedherein means a C₁ to C₃ alkyl group substituted with a carbamoyl groupin which two hydrogen atoms in the amino group are substituted with C₁to C₂ alkyl groups. Examples of the di-C₁ to C₂ alkylcarbamoyl C₁ to C₃alkyl group may include an N,N-dimethylcarbamoylmethyl group, anN-ethyl-N-methylcarbamoylmethyl group, a 2-(N,N-dimethylcarbamoyl)ethylgroup, a 2-(N-ethyl-N-methylcarbamoyl)ethyl group, a3-(N,N-dimethylcarbamoyl)propyl group, a 3-(N,N-diethylcarbamoyl)propylgroup and the like.

Examples of an “aromatic hydrocarbon cyclic group” as used herein mayinclude a phenyl group, an indenyl group, a 1-naphthyl group, a2-naphthyl group, an azulenyl group, a heptalenyl group, a biphenylgroup, an indacenyl group, an acenaphthyl group, a fluorenyl group, aphenalenyl group, a phenanthrenyl group, an anthracenyl group, abenzocyclooctenyl group and the like.

The term “aromatic heterocyclic group” as used herein means an aromaticcyclic structure containing a nitrogen atom, an oxygen atom, or a sulfuratom. Examples of the aromatic heterocyclic group may include a furylgroup, a thienyl group, a pyrrolyl group, an azepinyl group, a pyrazolylgroup, an imidazolyl group, an oxazolyl group, an isoxazolyl group, athiazolyl group, an isothiazolyl group, a 1,2,3-oxadiazolyl group, atriazolyl group, a tetrazolyl group, a thiadiazolyl group, a pyranylgroup, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, apyrazinyl group and the like. The above “heterocyclic group” may beannelated with another cyclic group. Examples of such a heterocyclicgroup may include an isobenzofuranyl group, a benzoxazolyl group, abenzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group,a chromenyl group, a chromanonyl group, a xanthenyl group, aphenoxathiinyl group, an indolizinyl group, an isoindolizinyl group, anindolyl group, an indazolyl group, a purinyl group, a quinolizinylgroup, an isoquinolyl group, a quinolyl group, a phthalazinyl group, anaphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, acarbazolyl group, a carbolinyl group, an acridinyl group, anisoindolinyl group and the like.

The term “halo-C₁ to C₆ alkyl group” as used herein means a C₁ to C₆alkyl group substituted with 1 to 5 halogen atoms of the same type ordifferent types. Examples of the halo-C₁ to C₆ alkyl group may include afluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a2-fluoroethyl group, a 2-chloroethyl group, a 2,2-difluoroethyl group, a1,1-difluoroethyl group, a 1,2-difluoroethyl group, a2,2,2-trifluoroethyl group, a 1,1,2,2,2-pentafluoroethyl group, a2,2,2-trichloroethyl group, a 3-fluoropropyl group, a 2-fluoropropylgroup, a 1-fluoropropyl group, a 3,3-difluoropropyl group, a2,2-difluoropropyl group, a 1,1-difluoropropyl group, a 4-fluorobutylgroup, a 5-fluoropentyl group, a 6-fluorohexyl group and the like.

No particular limitation is imposed on the groups acceptable as the“substituent(s)” in the “phenyl group optionally having substituent(s),”the “5-membered aromatic heterocyclic group optionally havingsubstituent(s),” the “6-membered aromatic heterocyclic group optionallyhaving substituent(s),” the “bicyclic aromatic heterocyclic group having8 or 9 atoms and optionally having substituent(s),” and the“heterocyclic group optionally having substituent(s),” so long as thesubstituent(s) are generally known substituent(s). Examples of thesesubstituent(s) may include halogen atoms, an amino group, a hydroxygroup, a cyano group, a nitro group, a carboxy group, C₁ to C₆alkoxycarbonyl groups, a formyl group, C₁ to C₆ acyl groups, C₁ to C₆alkyl groups, C₁ to C₆ alkylamino groups, C₁ to C₆ alkoxy groups, C₁ toC₆ alkylthio groups, C₃ to C₆ cycloalkyl groups, 4- to 10-memberedheterocycloalkyl groups, aromatic hydrocarbon cyclic groups optionallyhaving a halogen atom, aromatic heterocyclic groups, C₁ to C₆alkylcarbonylamino groups, C₃ to C₆ cycloalkylcarbonylamino groups, 4-to 10-membered heterocycloalkylcarbonylamino groups, aromatichydrocarbon cyclic carbonylamino groups, aromatic heterocycliccarbonylamino groups and the like.

No particular limitation is imposed on the groups acceptable as the“substituent(s)” in the “C₁ to C₆ alkoxy group optionally havingsubstituent(s),” the “C₁ to C₆ alkyl group optionally havingsubstituent(s),” the “C₁ to C₆ acyl group optionally havingsubstituent(s),” the “C₁ to C₆ alkylsulfanyl group optionally havingsubstituent(s),” the “C₁ to C₆ alkylsulfinyl group optionally havingsubstituent(s),” the “C₁ to C₆ alkylsulfonyl group optionally havingsubstituent(s),” the “C₃ to C₆ cycloalkyl group optionally havingsubstituent(s),” the “C₃ to C₆ cycloalkoxy group optionally havingsubstituent(s),” the “C₂ to C₆ alkenyl group optionally havingsubstituent(s),” the “C₁ to C₆ alkoxycarbonyl group optionally havingsubstituent(s),” the “aromatic heterocyclic C₁ to C₃ alkyl groupoptionally having substituent(s),” and the “phenyl C₁ to C₃ alkyl groupoptionally having substituent(s),” so long as the substituent(s) aregenerally known substituent(s). Examples of these substituent(s) mayinclude halogen atoms, an amino group, a hydroxy group, a cyano group, anitro group, a carboxy group, C₁ to C₆ alkoxycarbonyl groups, a formylgroup, C₁ to C₆ acyl groups, C₁ to C₆ alkyl groups, C₁ to C₆ alkylaminogroups, di-C₁ to C₆ alkylamino groups, C₁ to C₆ alkoxy groups, C₁ to C₆alkylthio groups, C₃ to C₆ cycloalkyl groups, 4- to 10-memberedheterocycloalkyl groups, aromatic hydrocarbon cyclic groups optionallyhaving a halogen atom, aromatic heterocyclic groups, C₁ to C₆alkylcarbonylamino groups, C₃ to C₆ cycloalkylcarbonylamino groups, 4-to 10-membered heterocycloalkylcarbonylamino groups, aromatichydrocarbon cyclic carbonylamino groups, aromatic heterocycliccarbonylamino groups and the like.

Hereinafter, the present embodiment will be described in more detail.

In the following, descriptions of the definitions of functional groupsincluded in general formulas may be omitted, and the definitions alreadydescribed may be quoted instead. The definitions quoted refer todefinitions in the description of the following embodiment.

As for the definitions of functional groups included in the generalformulas, the definition of a symbol is common to general formulascontaining this symbol, unless otherwise mentioned.

The present embodiment relates to a urea compound represented by thefollowing general formula (I) or a pharmacologically acceptable saltthereof.

In the formula (I), Ar¹ is a phenyl group optionally havingsubstituent(s), a 5-membered aromatic heterocyclic group optionallyhaving substituent(s), a 6-membered aromatic heterocyclic groupoptionally having substituent(s), or a bicyclic aromatic heterocyclicgroup having 8 or 9 atoms and optionally having substituent(s);

Ar² is a phenyl group optionally having substituent(s) (except for aphenyl group substituted only with halogen atom(s)), a 5-memberedaromatic heterocyclic group optionally having substituent(s), a6-membered aromatic heterocyclic group optionally having substituent(s),or a bicyclic aromatic heterocyclic group having 8 or 9 atoms andoptionally having substituent(s);

X is a group selected from the group consisting of the following a), b),and c),

a) an oxygen atom or a sulfur atom,

b) NR⁴, and

c) NOR⁴, wherein,

when X is b) or c), R⁴ is a hydrogen atom or a C₁ to C₆ alkyl groupoptionally having substituent(s);

R¹ is a hydrogen atom, a hydroxy group, a C₁ to C₆ alkoxy groupoptionally having substituent(s), or a C₁ to C₆ alkyl group optionallyhaving substituent(s);

R² and R³ are each independently a hydrogen atom or a C₁ to C₆ alkylgroup optionally having substituent(s) or R² and R³ together form a C₂to C₆ alkylene group; and

Each carbon atom marked with an asterisk is an asymmetric carbon atom.

The term “independently” means that at least two substituents presentmay be the same or different.

In the compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof, preferred substituents are as follows.

Preferably, Ar¹ is a group selected from the group consisting of thefollowing B1), B2), B3), B4), B5), B6), B7), B8), B9), B10), B11), andB12).

More preferably, Ar¹ is a group selected from the group consisting ofthe following B1), B2), B6a), B9a), and B9b).

R¹² is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group,a C₁ to C₆ alkyl group optionally having substituent(s), a C₁ to C₆alkoxy group optionally having substituent(s), a C₃ to C₆ cycloalkylgroup optionally having substituent(s), a C₃ to C₆ cycloalkoxy groupoptionally having substituent(s), a C₁ to C₆ acyl group optionallyhaving substituent(s), a C₂ to C₆ alkenyl group optionally havingsubstituent(s), a C₂ to C₆ alkynyl group optionally havingsubstituent(s), a C₁ to C₆ alkoxycarbonyl group, a C₁ to C₆alkylsulfanyl group optionally having substituent(s), a C₁ to C₆alkylsulfinyl group optionally having substituent(s), a C₁ to C₆alkylsulfonyl group optionally having substituent(s), —CONR¹⁰R¹¹,—NR¹⁰R¹¹, an aryloxy group, or a heterocyclic group optionally havingsubstituent(s). When R¹² is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogenatom, a C₁ to C₆ alkyl group optionally having substituent(s), a C₁ toC₆ acyl group optionally having substituent(s), or a C₁ to C₆alkylsulfonyl group optionally having substituent(s) and R¹¹ is ahydrogen atom or a C₁ to C₆ alkyl group optionally havingsubstituent(s), or R¹⁰ and R¹¹ may together form a C₃ to C₁₀heterocycloalkyl group.

R¹³ may be a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, or a C₁ to C₆ alkyl group.

When Ar¹ is B), each of R¹² and R¹³ is any of the above describedfunctional groups, or R¹² and R¹³ may together form a C₃ to C₅ alkylenegroup or a C₁ to C₂ alkylenedioxy group.

R¹⁴ and R¹⁵ are each independently a hydrogen atom, a halogen atom, acyano group, a C₁ to C₆ alkyl group, or a C₁ to C₆ alkoxy group.

One of W¹⁰ and W¹¹ is a nitrogen atom, and the other thereof is CH or anitrogen atom.

W¹² is an oxygen atom, a sulfur atom, or N—R¹⁶. When W¹² is N—R¹⁶, R¹⁶is a hydrogen atom or a C₁ to C₆ alkyl group.

W¹³ is CH or a nitrogen atom.

Preferably, one of W¹⁰ and W¹¹ is N, and the other thereof is CH.

W¹² is preferably an oxygen atom or a sulfur atom. W¹² is morepreferably a sulfur atom.

W¹³ is preferably CH.

Preferably, R¹² is a hydrogen atom, a halogen atom, a cyano group, a C₁to C₆ alkyl group optionally having substituent(s), or a C₁ to C₆ alkoxygroup optionally having substituent(s). R¹² is more preferably ahydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a C₁ toC₃ alkyl group, or a C₁ to C₆ alkoxy group and is particularly morepreferably a hydrogen atom, a fluorine atom, a chlorine atom, a cyanogroup, or a C₁ to C₃ alkyl group.

Preferably, R¹³ is a hydrogen atom, a hydroxy group, a halogen atom, ora C₁ to C₆ alkyl group. R¹³ is more preferably a hydrogen atom, afluorine atom, or a chlorine atom.

Preferably, R¹⁴ is a hydrogen atom, a fluorine atom, a chlorine atom, aC₁ to C₃ alkyl group, a methoxy group, or an ethoxy group.

R¹⁵ is preferably a hydrogen atom, a fluorine atom, or a chlorine atomand particularly preferably a hydrogen atom.

Preferably, Ar² is a group selected from the group consisting of thefollowing A1), A2), A3), A4), A5), A6), A7), A8), A9), and A10)

Ar² is more preferably a group selected from the group consisting of thefollowing A1), A2a), A3), and A7a).

W¹ is a nitrogen atom or CH optionally substituted with a hydrogen atom,with a halogen atom, or with a C₁ to C₆ alkyl group optionally havingsubstituent(s). W² is CH or a nitrogen atom.

W³ is an oxygen atom, a sulfur atom, or NH optionally substituted with aC₁ to C₆ alkyl group.

W⁴ is CH or a nitrogen atom.

W⁵ is CH₂, an oxygen atom, or a sulfur atom.

W⁶ is C═O, CH₂, CF₂, CHOH, NH optionally substituted with a C₁ to C₆alkyl group, SO, SO₂, an oxygen atom, or a sulfur atom.

W⁷ is NH optionally substituted with a C₁ to C₆ alkyl group or C═O.

W⁸ is C═O when W⁷ is NH optionally substituted with a C₁ to C₆ alkylgroup and is NH optionally substituted with a C₁ to C₆ alkyl group whenW⁷ is C═O.

W⁹ is a nitrogen atom or N═O.

R⁶ is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, aC₁ to C₆ alkyl group optionally having substituent(s), a C₁ to C₆ alkoxygroup optionally having substituent(s), a C₁ to C₆ acyl group optionallyhaving substituent(s), a C₁ to C₆ alkylsulfanyl group optionally havingsubstituent(s), a C₁ to C₆ alkylsulfinyl group optionally havingsubstituent(s), a C₁ to C₆ alkylsulfonyl group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s),—CONR¹⁰R¹¹, or —NR¹⁰R¹¹. When R⁶ is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is ahydrogen atom, a C₁ to C₆ alkyl group optionally having substituent(s),a C₁ to C₆ acyl group optionally having substituent(s), or a C₁ to C₆alkylsulfonyl group optionally having substituent(s) and R¹¹ is ahydrogen atom or a C₁ to C₆ alkyl group optionally havingsubstituent(s), or R¹⁰ and R¹¹ may together form a C₃ to C₁₀heterocycloalkyl group.

R⁷ is a hydrogen atom, a halogen atom, a C₁ to C₆ alkyl group optionallyhaving substituent(s), or a C₁ to C₆ alkoxy group optionally havingsubstituent(s).

R⁸ is a hydrogen atom, a halogen atom, or a C₁ to C₆ alkyl groupoptionally having substituent(s).

R⁹ is a hydrogen atom or a C₁ to C₆ alkyl group.

m is 0 or 1.

n is 0 or 1.

When Ar² is A1), combinations of the substituents R⁶, R⁷ and R⁸ excludea combination of a hydrogen atom and a halogen atom.

Preferably, W¹ is CH or N. W¹ is more preferably N.

Preferably, W² is CH or N. W² is more preferably CH.

Preferably, W³ is an oxygen atom or a sulfur atom. W³ is more preferablya sulfur atom.

Preferably, W⁵ is CH₂ or O.

Preferably, W⁶ is C═O, CH₂, CF₂, CHOH, or an oxygen atom. W⁶ is morepreferably C═O, CH₂, CHOH, or an oxygen atom and particularly preferablyan oxygen atom.

Preferably, W⁹ is a nitrogen atom.

Preferably, m is 0.

Preferably, R⁶ is a hydrogen atom, a halogen atom, a cyano group, a C₁to C₆ alkyl group optionally having substituent(s), a C₁ to C₆ alkoxygroup optionally having substituent(s), a halo-C₁ to C₆ alkoxy group, aC₁ to C₆ acyl group optionally having substituent(s), a C₁ to C₆alkylsulfanyl group optionally having substituent(s), a C₁ to C₆alkylsulfinyl group optionally having substituent(s), —CONR¹⁰R¹¹, or—NR¹⁰R¹¹.

Preferably, when R⁶ is —CONR¹⁰R¹¹ or —NR¹⁰R¹¹, R¹⁰ is a hydrogen atom, aC₁ to C₆ alkyl group, or a C₁ to C₆ acyl group and R¹ is a hydrogen atomor a C₁ to C₆ alkyl group, or R¹⁰ and R¹¹ may together formapyrrolidinyl group, a piperidinyl group, a piperazinyl group, or amorpholinyl group.

R⁶ is more preferably a hydrogen atom, a fluorine atom, a chlorine atom,a cyano group, a C₁ to C₆ alkoxy group, a halo-C₁ to C₆ alkoxy group, aC₁ to C₆ alkyl group, a C₁ to C₆ alkylsulfanyl group, or a C₁ to C₆alkylsulfinyl group and is particularly preferably a cyano group, anethyl group, or a C₁ to C₃ alkoxy group.

Preferably, R⁷ is a hydrogen atom, a halogen atom, a C₁ to C₆ alkylgroup optionally having substituent(s), or a C₁ to C₆ alkoxy groupoptionally having substituent(s). R⁷ is more preferably a hydrogen atom,a halogen atom, or a C₁ to C₃ alkyl group and is particularly preferablya hydrogen atom, a fluorine atom, or a chlorine atom.

Preferably, R⁸ is a hydrogen atom, a halogen atom, or a C₁ to C₆ alkylgroup optionally having substituent(s). R⁸ is more preferably a hydrogenatom, a halogen atom, or a C₁ to C₆ alkyl group and is particularlypreferably a hydrogen atom, a fluorine atom, a chlorine atom, or a C₁ toC₃ alkyl group.

Preferably, R⁹ is a hydrogen atom, a methyl group, or an ethyl group.

Preferably, X is an oxygen atom, NOH, N—(C₁ to C₃ alkyl group), N—O—(C₁to C₃ alkyl group), or N—O-(hydroxy C₁ to C₄ alkyl group). X is morepreferably an oxygen atom, NMe, NOMe, NOH, or NOCH₂CH₂OH and isparticularly preferably an oxygen atom.

Preferably, R¹ is a hydrogen atom, a hydroxy group, a C₁ to C₆ alkylgroup, a C₁ to C₆ alkoxy group, a halo-C₁ to C₆ alkyl group, a hydroxyC₁ to C₆ alkyl group, a carboxy C₁ to C₆ alkyl group, a carbamoyl C₁ toC₆ alkyl group, a monoalkylcarbamoyl C₁ to C₆ alkyl group, or adialkylcarbamoyl C₁ to C₆ alkyl group. R¹ is more preferably a hydrogenatom, a hydroxy group, a C₁ to C₃ alkyl group, a C₁ to C₃ alkoxy group,or a hydroxy C₁ to C₄ alkyl group and is particularly preferably ahydrogen atom, a methyl group, an ethyl group, or a hydroxyethyl group.

Preferably, R² is a hydrogen atom or a C₁ to C₃ alkyl group. R² is morepreferably a hydrogen atom or a methyl group and is particularlypreferably a hydrogen atom.

Preferably, R³ is a hydrogen atom or a C₁ to C₃ alkyl group. R³ is morepreferably a hydrogen atom or a methyl group and is particularlypreferably a hydrogen atom.

Preferred examples of the compound of the present embodiment may includethe following compounds:

-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(3,4-difluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(2,4-difluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   1-[(3S*,4R*)-4-(2-chloro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxy-2-methylphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(3,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(7-fluorochroman-6-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(3-fluoro-5-methoxypyridin-2-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(5-methoxythiophen-2-yl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylthiophenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-methylsulfonylphenyl)urea;-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-methoxyphenyl)urea;-   (−)-1-(benzo[d][1,3]dioxole-5-yl)-3-[(3R*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(5-chlorothiazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyrimidin-4-yl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyridin-2-yl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyridin-3-yl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyrimidin-5-yl)urea;-   (−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(5-chloropyridin-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyrazin-2-yl)urea;-   (−)-1-(benzo[d]thiazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(benzo[b]thiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(benzo[d]oxazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(5-methylisoxazol-3-yl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(2-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(5-methylthiophen-2-yl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,5S*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,5R*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;-   1-[(3S*,4R*)-4-(4-ethyl-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-2-oxo-4-phenylpyrrolidin-3-yl]urea;-   (+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(3-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(2-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-1-[(3R*,4S*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-fluorophenyl)-3-[(3R*,4S*,5S*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-fluorophenyl)-3-[(3R*,4S*,5R*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-fluorophenyl)-3-[(3R*,4S*)-4-(5-methoxythiophen-2-yl)-2-oxopyrrolidin-3-yl]urea;-   (+)-1-{(3R*,4S*)-4-[4-(difluoromethoxy)phenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;-   (±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (+)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dim    ethyl-2-oxopyrrolidin-3-yl]urea;-   (−)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dim    ethyl-2-oxopyrrolidin-3-yl]urea;-   (+)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea;-   (−)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea;-   (+)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea;-   (−)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylsulfinylphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylsulfonylphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(trifluoromethoxy)phenyl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea;-   (−)-1-[4-(tert-butyl)phenyl]-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}benzoic    acid ethyl ester;-   (−)-1-[(1,1′-biphenyl)-4-yl]-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-acetylphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-phenoxyphenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3,4-difluorophenyl)urea;-   (−)-1-(5-chlorothiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(p-tolyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(hydroxymethyl)phenyl]urea;-   (−)-4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}-N-methylbenzamide;-   (−)-1-[(3S*,4R*)-1-ethyl-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}acetic    acid ethyl ester;-   2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionic    acid ethyl ester;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-1-(1-hydroxy-2-methylpro    pan-2-yl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic    acid ethyl ester (isomer A);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)    ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic acid    ethyl ester (isomer B);-   (+)-trans-1-(4-chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-trans-1-(4-chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-trans-1-(4-chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}acetic    acid;-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylacetamide;-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic    acid (isomer A);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylpropionamide    (isomer A);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic    acid (isomer B);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylpropionamide    (isomer B);-   2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionic    acid;-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N,2-dimethylpropionamide;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (+)-1-(4-fluorophenyl)-3-[(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}-N,N-dimethylbenzamide;-   (−)-3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}-N-methylbenzamide;-   (−)-1-[(3S*,4R*)-4-(4-cyano-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}benzamide;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*,Z)-4-(2-fluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-{(3S*,4R*,Z)-2-[(2-hydroxyethoxy)imino]-4-(4-methoxyphenyl)pyrrolidin-3-yl}urea;-   (−)-1-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methylimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (+)-1-(4-fluorophenyl)-3-[(3R*,4S*,    Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(2-hydroxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea;-   1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-hydroxyphenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-methylisothiazol-5-yl)urea;-   (−)-1-(4-cyclopropylphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(trifluoromethyl)phenyl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-hydroxy-4-methylphenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluoro-3-hydroxyphenyl)urea;-   (−)-1-(4-chloro-3-hydroxyphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   1-(4-cyano-3-hydroxyphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   1-{(3S*,4R*)-4-[4-(difluoromethoxy)-2,6-difluorophenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(6-fluorobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   1-[(3S*,4R*)-4-(4,6-difluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(benzo[b]thiophene-2-yl)-3-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-ethylphenyl)urea;-   (−)-1-(3-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(5-chlorothiophen-2-yl)-3-[(3S*,4R*)-4-(3-fluoro-5-methoxypyridine-2-yl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-fluorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-2-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}acetic    acid;-   (−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}acetic    acid;-   (−)-2-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-N-methylacetamide;-   (−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}acetamide;-   (−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-2-methylpropanoic    acid;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(benzo[b]thiophene-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-phenylurea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(p-tolyl)urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(benzo[b]thiophene-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxo-1-propylpyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-1-benzyl-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxo-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-[(methyl    sulfonyl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;-   (−)-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}methanesulfonamide;-   (−)-2-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}acetic    acid ethyl ester;-   (−)-1-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-[(5-meth    yloxazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;-   (−)-1-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluoro    phenyl)urea;-   (−)-1-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}acetic    acid ethyl ester;-   (−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-2-methylpropanoic    acid ethyl ester;-   (−)-1-[(3S*,4R*)-1-(cyclopropylmethyl)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-1-(cyanomethyl)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methoxy-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   1-[(3S*,4R*)-4-(2,6-difluoro-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(p-tolyl)urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]urea;-   (−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]urea;-   (−)-1-(benzo[b]thiophen-2-yl)-3-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]urea;-   (−)-1-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}-3-(p-tolyl)urea;-   (−)-1-(4-cyanophenyl)-3-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}urea;-   (−)-1-(6-chloropyridin-3-yl)-3-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}urea;-   (−)-1-(benzo[b]thiophen-2-yl)-3-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}urea;-   (−)-1-{(3R*,4S*)-3-(2,6-difluoro-4-methoxyphenyl)-5-[(1-methyl-1H-pyrazol-3-yl)amino]-3,4-dihydro-2H-pyrrole-4-yl}-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(morpholinoimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   1-[(3R*,4S*)-3-(2,6-difluoro-4-methoxyphenyl)-5-(phenylamino)-3,4-dihydro-2H-pyrrole-4-yl]-3-(4-fluorophenyl)urea;-   (−)-1-((3S*,4R*,Z)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl)-3-(4-fluorophenyl)urea;-   3-((Z)-{(3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]pyrrolidin-2-ylidene}amino)propanoic    acid ethyl ester;-   (−)-1-((3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(hydroxyimino)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-ethynylphenyl)urea;-   (−)-1-{(3S*,4R*)-4-[2,6-difluoro-4-(methylamino)phenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;    and-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea.

More preferred examples of the compound of the present embodiment mayinclude the following compounds:

-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(3,4-difluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   1-[(3S*,4R*)-4-(2-chloro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxy-2-methylphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(3,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(3-fluoro-5-methoxypyridin-2-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(5-methoxythiophen-2-yl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylthiophenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-methoxyphenyl)urea;-   (−)-1-(5-chlorothiazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(5-chloropyridin-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(benzo[b]thiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(5-methylthiophen-2-yl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,5S*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,5R*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;-   (+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-2-oxo-4-phenylpyrrolidin-3-yl]urea;-   (±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(trifluoromethoxy)phenyl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-phenoxyphenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3,4-difluorophenyl)urea;-   (−)-1-(5-chlorothiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(p-tolyl)urea;-   (−)-1-[(3S*,4R*)-1-ethyl-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-1-(1-hydroxy-2-methylpro    pan-2-yl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (±)-trans-1-(4-chlorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (+)-trans-1-(4-chlorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-trans-1-(4-chlorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylacetamide;-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic    acid (isomer A);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylpropionamide    (isomer A);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic    acid (isomer B);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylpropionamide    (isomer B);-   (−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N,2-dimethylpropionamide;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (+)-1-(4-fluorophenyl)-3-[(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}benzamide;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*,Z)-4-(2-fluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-{(3S*,4R*,Z)-2-[(2-hydroxyethoxy)imino]-4-(4-methoxyphenyl)pyrrolidin-3-yl}urea;-   (−)-1-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}-3-(4-fluorophenyl)urea;-   (−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methylimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;-   (−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(2-hydroxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-hydroxy-4-methylphenyl)urea;-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluoro-3-hydroxyphenyl)urea;-   (−)-1-(4-chloro-3-hydroxyphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]urea;-   (−)-1-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}-3-(p-tolyl)urea;    and-   (−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-phenylurea.

If necessary, the compound (I) of the present embodiment can beconverted to a pharmacologically acceptable salt according to a usualmethod. The pharmacologically acceptable salt means a salt with apharmacologically acceptable nontoxic base or acid (for example, aninorganic or organic base or an inorganic or organic acid).

Examples of the salt derived from a pharmacologically acceptablenontoxic base may include: salts with inorganic bases such as sodiumsalts, potassium salts, calcium salts, magnesium salts and the like; andsalts with organic bases such as piperidine, morpholine, pyrrolidine,arginine, lysine and the like.

Examples of the salt derived from a pharmacologically acceptablenontoxic acid may include: acid addition salts with mineral acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid andthe like; and acid addition salts with organic acids such as formicacid, acetic acid, maleic acid, fumaric acid, succinic acid, lacticacid, malic acid, tartaric acid, citric acid, methanesulfonic acid,p-toluenesulfonic acid, salicylic acid, stearic acid, palmitic acid andthe like.

The compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof may be present as a hydrate or a solvate. Anyhydrate and solvate formed from the urea derivative represented by thegeneral formula (I) above, including any of the preferred compoundsspecifically described above, or a salt thereof are included in thescope of the present invention. Examples of the solvent that can formthe solvate may include methanol, ethanol, 2-propanol, acetone, ethylacetate, dichloromethane, diisopropyl ether and the like.

The compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof may be a racemate and also includes theiroptically active substances, stereoisomers, and rotational isomers.

When the compound (I) of the present embodiment is one of its opticalisomers having one or more asymmetric carbon atom, the configuration ofeach asymmetric carbon atoms in the compound (I) of the presentembodiment is any of the R configuration and the S configuration. Any ofthe optical isomers is included in the present invention, and a mixtureof these optical isomers is also included in the present invention. Amixture of optically active substances may be a racemate formed of equalamounts of the optical isomers, and this racemate is also included inthe scope of the present invention. When the compound (I) of the presentembodiment is a solid or crystalline racemate, the racemate, a racemicmixture, a racemic solid solution are included in the scope of thepresent invention.

When the compound (I) of the present embodiment includes geometricalisomers, all the geometrical isomers are included in the presentinvention.

When the compound (I) of the present embodiment includes tautomers, allthe tautomers are included in the present invention.

Pharmacologically acceptable salts of the compound (I) include protontautomers.

The compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof may be a compound labeled with an isotope (forexample, ³H, ¹⁴C, ³⁵S and the like). Such a compound is also included inthe present invention.

The compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof may be a deuterium-substituted compound in which¹H is substituted with ²H(D). Such a compound is also included in thepresent invention.

The term “FPRL1 agonist effect” in the present embodiment means agonistactivity obtained by the action on formyl peptide receptor like 1(FPRL1). The compound (I) of the present embodiment or apharmacologically acceptable salt thereof exhibits superior agonistactivity in, for example, a test of calcium influx intoFPRL1-overexpressing cells. Therefore, it can be understood that thecompound (I) of the present embodiment or a pharmacologically acceptablesalt thereof is useful as a therapeutic or prophylactic agent forinflammatory diseases, chronic airway diseases, cancers, septicemia,allergic symptoms, HIV retrovirus infection, circulatory disorders,neuroinflammation, nervous disorders, pains, prion diseases,amyloidosis, immune disorders and the like.

Method of Producing the Compound (I) of the Present Embodiment

The compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof can be produced, for example, in accordance withany of methods described in the following schemes 1 to 17, methodssimilar thereto, methods described in other literatures, and methodssimilar thereto.

Synthesis of Compound (Ia)

The compound (I) of the present embodiment when X is O (this compound ishereinafter referred to as the compound (Ia)) can be produced inaccordance with any of methods described in scheme 1, methods similarthereto, methods described in other literatures, and methods similarthereto.

In the above formulas, Ar¹, Ar², R¹, R², and R³ are as described above,and each carbon atom marked with an asterisk is an asymmetric carbonatom.

Step 1-1

This step is a step of reacting the compound (1) with the compound (2)to produce the compound (Ia). The compound (Ia) can be produced by, forexample, allowing diphenylphosphoryl azide (DPPA) and the like to act onthe compound (1) in a solvent in the presence or absence of a base andthen reacting the compound (2) with the obtained product.

The above reaction is usually performed in a solvent that does notadversely affect the reaction, and examples of the solvent used mayinclude benzene, toluene, tetrahydrofuran, acetonitrile, dioxane, mixedsolvents of them and the like. Examples of the base used may includetrimethylamine, triethylamine, N-methylmorpholine and the like. Theamount of the base used is usually about 0.5 to about 100 molarequivalents with respect to 1 mole of the compound and preferably about1 to about 5 molar equivalents. The reaction temperature can usually beperformed at −10° C. to the reflux temperature of the solvent and isperformed preferably at 20° C. to 120° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature, or the like, but is usually 10 minutes to 3 days.

The compound (1) used in this step can be produced in accordance withany of methods described below in detail, methods similar thereto,methods described in other literatures, and methods similar thereto.

Further, the compound (2) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto.

Step 1-2

This step is a step of reacting the compound (3) with the compound (4)to produce the compound (Ia). The compound (Ia) can be produced by, forexample, reacting the compound (3) with the compound (4) in a solvent inthe presence or absence of a base. The amount of the compound (4) usedis about 0.5 to about 10 molar equivalents with respect to 1 mole of thecompound (3) and is preferably about 1 to about 2 molar equivalents.

The above reaction is usually performed in a solvent that does notadversely affect the reaction, and examples of the solvent used mayinclude dichloromethane, 1,2-dichloroethane, benzene, toluene,tetrahydrofuran, ethyl acetate, methanol, water, mixed solvents of themand the like. Examples of the base used may include alkali metalhydrides such as lithium hydride, sodium hydride, potassium hydride andthe like, alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide and the like, hydrogen carbonates such as sodium hydrogencarbonate, potassium hydrogen carbonate and the like, carbonates such assodium carbonate, potassium carbonate and the like, organic acid saltssuch as sodium acetate and the like, tertiary amines such astrimethylamine, triethylamine, N-methylmorpholine and the like, andaromatic amines such as pyridine, picoline, N,N-dimethyl aniline and thelike. The amount of the base used is usually about 1 to about 100 molarequivalents with respect to 1 mole of the compound and preferably about1 to about 5 molar equivalents. The reaction temperature can usually beperformed at −20° C. to the reflux temperature of the solvent and isperformed preferably at 0° C. to 50° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 10 minutes to 48 hours.

The compound (3) used in this step can be produced in accordance withany of methods described below in detail, methods similar thereto,methods described in other literatures, and methods similar thereto.

Further, the compound (4) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto.

Synthesis of Compound (Ib)

The compound (I) of the present embodiment when X is O and R¹ is H (thiscompound may hereinafter be referred to as the compound (Ib)) can beproduced in accordance with any of methods described in scheme 2,methods similar thereto, methods described in other literatures, andmethods similar thereto.

In the above formulas, Ar¹, Ar², R², and R³ are as described above, andeach carbon atom marked with an asterisk is an asymmetric carbon atom.

Step 2-1

This step is a step of producing the compound (Ib) from the compound(1a). The compound (Ib) by the step 2-1 can be produced in accordancewith any of the method described in step 1-1 of scheme 1, methodssimilar thereto, methods described in other literatures, and methodssimilar thereto.

Step 2-2

This step is a step of converting the carboxy group in the compound (1a)to a primary amine to produce the compound (3a). The compound (3a) canbe produced by, for example, allowing diphenylphosphoryl azide (DPPA)and the like to act on the compound (1a) in a solvent A in the presenceor absence of a base and then reacting the product obtained with an acidin a solvent B. Examples of the solvent A may include benzene, toluene,tetrahydrofuran, acetonitrile, dioxane, mixed solvents of them and thelike. Examples of the solvent B may include dioxane, water and the like.Examples of the base used may include trimethylamine, triethylamine,N-methylmorpholine and the like. Examples of the acid used may includeconc. hydrochloric acid, conc. sulfuric acid and the like. The reactiontemperature can usually be performed at −10° C. to the refluxtemperature of the solvent and is performed preferably at 0° C. to 100°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually30 minutes to 3 days.

Step 2-3

This step is a step of producing the compound (5) from the compound(1a). The compound (5) can be produced by, for example, allowingdiphenylphosphoryl azide (DPPA) and the like to act on the compound (1a)in a solvent in the presence or absence of a base and then reacting theobtained product with benzyl alcohol in a solvent or without anysolvent. Examples of the solvent used may include benzene, toluene,tetrahydrofuran, acetonitrile, dioxane, mixed solvents of them and thelike. Examples of the base used may include trimethylamine,triethylamine, N-methylmorpholine and the like. The reaction temperaturecan usually be performed at 0° C. to the reflux temperature of thesolvent and is performed preferably at 10° C. to 120° C. The reactiontime varies depending on the starting materials used, the solvent used,the reaction temperature or the like, but is usually 30 minutes to 3days.

Step 2-4

This step is a step of deprotecting the Cbz (benzyloxycarbonyl) group inthe compound (5) to produce the compound (3a). The compound (3a) can beproduced by, for example, hydrogenating the compound (5) in a solvent inthe presence of a catalyst such as 10% palladium on carbon (10% Pd—C).Examples of the solvent used may include methanol, ethanol,dichloromethane, tetrahydrofuran, ethyl acetate, mixed solvents of themand the like. The reaction temperature can usually be performed at 0° C.to the reflux temperature of the solvent and is performed preferably at10° C. to 40° C. The reaction time varies depending on the startingmaterials used, the solvent used, the reaction temperature or the like,but is usually 30 minutes to 3 days.

Step 2-5

This step is a step of producing the compound (Ib) from the compound(3a). The compound (Ib) by the step 2-5 can be produced in accordancewith any of the method described in step 1-2 of scheme 1, methodssimilar thereto, methods described in other literatures, and methodssimilar thereto.

Synthesis of Compound (1b)

The compound (1b) among the compound (1) when R³ is H can be producedfrom the compound (6) in accordance with any of methods described inscheme 3, methods similar thereto, methods described in otherliteratures, and methods similar thereto.

In the above formulas, Ar² and R² are as described above; Q¹ is a C₁₋₆alkyl group and the like, and each carbon atom marked with an asteriskis an asymmetric carbon atom.

Step 3-1

This step is a step of reacting the compound (6) with the compound (7)to produce the compound (8). The compound (8) can be produced by, forexample, reacting the compound (6) with the compound (7) in acetic acidin the presence of ammonium acetate. The reaction temperature canusually be performed at 20° C. to the reflux temperature of the solventand is performed preferably at 80° C. to 110° C. Alternatively, thecompound (8) can be produced by reacting the compound (6) with thecompound (7) in 2-hydroxyethylammonium formate (2-HEAF). The reactiontemperature can usually be performed at 0° C. to 80° C. and is performedpreferably at 10° C. to 50° C. The reaction time varies depending on thestarting materials used, the solvent used, the reaction temperature orthe like, but is usually 30 minutes to 3 days.

The compound (6) and the compound (7) used in this step may be acommercially available, or can also be produced in accordance with anyof methods described in other literatures, and methods similar thereto.

Step 3-2

This step is a step of reacting the compound (8) with a malonic ester(9) to produce the compound (10). The compound (10) can be produced by,for example, reacting the compound (8) with the compound (9) in asolvent in the presence of a catalyst. Examples of the solvent used mayinclude benzene, toluene, tetrahydrofuran, methyl t-butyl ether,acetonitrile, methanol, ethanol, ethyl acetate and the like. Examples ofthe catalyst used may include nickel(II)bis[(S,S)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide, nickel (II)bis[(R,R)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide,1-(3,5-bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-(dimethylamino)cyclohexyl)thiourea,and1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl)thioureathat can be obtained according to methods described in Non PatentLiterature. The amount of the catalyst used is usually 0.001 to 0.2moles with respect to 1 mole of the compound (8). The reactiontemperature can usually be performed at −0° C. to the reflux temperatureof the solvent and is performed preferably at 10° C. to 50° C. Thereaction time varies depending on the starting materials used, thesolvent used, the reaction temperature or the like, but is usually 30minutes to 7 days.

Further, the compound (9) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto. Also, thecompound (8) may be a commercially available in addition to thatobtained in step 3-1, or can be produced in accordance with any ofmethods described in other literatures, and methods similar thereto.

Step 3-3

This step is a step of producing the compound (11) from the compound(10). The compound (11) can be produced by, for example, allowing sodiumborohydride (NaBH₄) to act on the compound (10) in a solvent in thepresence of nickel(II) chloride hexahydrate (NiCl₂.6H₂O). Examples ofthe solvent used may include methanol, ethanol, tetrahydrofuran, methylt-butyl ether and the like. The reaction temperature can usually beperformed at −30° C. to the reflux temperature of the solvent and isperformed preferably at 0° C. to 80° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

Step 3-4

This step is a step of hydrolyzing the ester moiety of the compound (11)to produce the compound (1b). The compound (1b) can be produced by, forexample, treating the compound (11) with a base in a solvent. Examplesof the solvent used may include water, methanol, ethanol, propanol,2-propanol, butanol, tetrahydrofuran, mixed solvents of them and thelike. Examples of the base used may include lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like. The reaction temperaturecan usually be performed at 0° C. to the reflux temperature of thesolvent and is performed preferably at 10° C. to 70° C. The reactiontime varies depending on the starting materials used, the solvent used,the reaction temperature or the like, but is usually 30 minutes to 3days.

Synthesis of Compound (1c)

The compound (1) when R² and R³ are not H (this compound may hereinafterbe referred to as the compound (1c)) can be produced from the compound(6) in accordance with any of methods described in scheme 4, methodssimilar thereto, methods described in other literatures, and methodssimilar thereto.

In the above formulas, Ar² and Q¹ are as described above, R^(2′) andR^(3′) are each independently a C₁₋₆ alkyl group optionally havingsubstituent(s) or together form a C₂ to C₆ alkylene group, and eachcarbon atom marked with an asterisk is an asymmetric carbon atom.

Step 4-1

This step is a step of reacting the compound (6) with the compound (9)to produce the compound (12). The compound (12) can be produced by, forexample, reacting the compound (6) with the compound (9) in a solvent inthe presence of a base. Examples of the solvent used may includebenzene, toluene, dimethyl sulfoxide, N,N-dimethylformamide, mixedsolvents of them and the like. Examples of the base used may includealiphatic amines such as piperidine, pyrrolidine, triethylamine,N-methylmorpholine and the like, aromatic amines such as pyridine,picoline, N,N-dimethyl aniline and the like, and organic acid salts suchas piperidinium acetate, ammonium acetate and the like. The reactiontemperature can usually be performed at 0° C. to the ref lux temperatureof the solvent and is performed preferably at 70° C. to 110° C. Thereaction time varies depending on the starting materials used, thesolvent used, the reaction temperature or the like. and is usually 30minutes to 3 days.

Further, the compound (6) and the compound (9) used in this step may bea commercially available, or can be produced in accordance with any ofmethods described in other literatures, and methods similar thereto.

Step 4-2

This step is a step of reacting the compound (12) with the compound (13)to produce the compound (14). The compound (14) can be produced by, forexample, reacting the compound (12) with the compound (13) in a solventin the presence of a base. Examples of the solvent used may includetoluene, benzene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide,N,N-dimethylformamide, mixed solvents of them and the like. Examples ofthe base used may include alumina-treated potassium fluoride (KF—Al₂O₃)and the like. The reaction temperature can usually be performed at 0° C.to the ref lux temperature of the solvent and is performed preferably at10° C. to 40° C. The reaction time varies depending on the startingmaterials used, the solvent used, the reaction temperature or the like,but is usually 30 minutes to 3 days.

Step 4-3

This step is a step of producing the compound (15) from the compound(14). The compound (15) can be produced in accordance with any of themethod described in step 3-3 of scheme 3, methods similar thereto,methods described in other literatures, and methods similar thereto.

Step 4-4

This step is a step of hydrolyzing the ester moiety of the compound (15)to produce the compound (1c). The compound (1c) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compound (3b)

The compound (3) when R³ is H (this compound may hereinafter be referredto as the compound (3b)) can be produced from the compound (8) inaccordance with any of methods described in scheme 5, methods similarthereto, methods described in other literatures, and methods similarthereto.

In the above formulas, Ar², R² and Q¹ are as described above, and eachcarbon atom marked with an asterisk is an asymmetric carbon atom.

Step 5-1

This step is a step of reacting the compound (8) with the compound (16)to produce the compound (17). The compound (17) can be produced by, forexample, reacting the compound (16) with the compound (8) in a solventin the presence of a base. Examples of the solvent used may includetetrahydrofuran, hexane, mixed solvents of them and the like. Examplesof the base used may include organolithiums such as lithiumdiisopropylamide (LDA) lithium hexamethyl disilazide (LHMDS) and thelike. The reaction temperature can usually be performed at −78° C. tothe reflux temperature of the solvent and is performed preferably at−78° C. to 30° C. The reaction time varies depending on the startingmaterials used, the solvent used, the reaction temperature or the like,but is usually 30 minutes to 3 days.

Further, the compound (8) and the compound (16) used in this step may bea commercially available, or can be produced in accordance with any ofmethods described in other literatures, and methods similar thereto.

Step 5-2

This step is a step of converting the imine moiety of the compound (17)to produce the compound (18). The compound (18) can be produced by, forexample, reacting the compound (17) with water in acetic acid and thenreacting the obtained product with di-tert-butyl dicarbonate ((Boc)₂O)in a solvent in the presence of a base. Examples of the solvent used mayinclude water, methanol, ethanol, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, 1,4-dioxane, acetonitrile, mixed solvents of themand the like. Examples of the base used may include triethylamine,sodium hydrogen carbonate, sodium carbonate and the like. The reactiontemperature can usually be performed at 0° C. to the ref lux temperatureof the solvent and is performed preferably at 10° C. to 70° C. Thereaction time varies depending on the starting materials used, thesolvent used, the reaction temperature or the like, but is usually 30minutes to 3 days.

Step 5-3

This step is a step of producing the compound (19) from the compound(18). The compound (19) can be produced in accordance with any of themethod described in step 3-3 of scheme 3, methods similar thereto,methods described in other literatures, and methods similar thereto.

Step 5-4

This step is a step of deprotecting the tert-butoxycarbonyl (Boc) groupin the compound (19) to produce the compound (3b). The compound (3b) canbe produced by, for example, reacting the compound (19) with an acidsuch as trifluoroacetic acid (TFA) or hydrogen chloride in a solvent.Examples of the solvent used may include dichloromethane, dioxane, ethylacetate, methanol, water, mixed solvents of them and the like. Thereaction temperature can usually be performed at 0° C. to the refluxtemperature of the solvent and is performed preferably at 0° C. to 60°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually30 minutes to 3 days.

Synthesis of Compound (1d)

The compound (1) when R¹ is a C₁ to C₆ alkyl group (this compound mayhereinafter be referred to as the compound (1d)) can be produced fromthe compound (20) in accordance with any of methods described in scheme6, methods similar thereto, methods described in other literatures, andmethods similar thereto.

In the above formulas, Ar², R², R³, and Q¹ are as described above, R^(a)is a C₁₋₆ alkyl group, W is an leaving group such as a chlorine atom, abromine atom, an iodine atom, a methane sulfonyloxy group, atrifluoromethane sulfonyloxy group and the like, and each carbon atommarked with an asterisk is an asymmetric carbon atom.

Step 6-1

This step is a step of chlorinating the compound (20) to produce thecompound (21). The compound (21) can be produced by, for example,reacting the compound (20) with sulfuryl chloride (SO₂Cl₂) in a solvent.Examples of the solvent used may include tetrahydrofuran and the like.The reaction temperature can usually be performed at 0° C. to the refluxtemperature of the solvent and is performed preferably at 20° C. to 70°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually30 minutes to 3 days.

The compound (20) used in this step can be produced in accordance withany of methods described in scheme 3 or 4, methods similar thereto,methods described in other literatures, and methods similar thereto.

Step 6-2

This step is a step of reacting the compound (21) with the compound (22)to produce the compound (23). The compound (23) can be produced by, forexample, reacting the compound (21) with the compound (22) in a solventin the presence of a base. Examples of the solvent used may includetetrahydrofuran, N,N-dimethylformamide, mixed solvents of them and thelike. Examples of the base used may include alkali metal hydrides suchas lithium hydride, sodium hydride and the like, alkali metal hydroxidessuch as sodium hydroxide, potassium hydroxide and the like, andcarbonates such as potassium carbonate, cesium carbonate and the like.The reaction temperature can usually be performed at −10° C. to thereflux temperature of the solvent and is performed preferably at 0° C.to 60° C. The reaction time varies depending on the starting materialsused, the solvent used, the reaction temperature or the like, but isusually 30 minutes to 3 days.

The compound (22) used in this step may be a commercially available, orcan also be produced in accordance with any of methods described inother literatures, and methods similar thereto.

Step 6-3

This step is a step of dechlorinating the compound (23) to produce thecompound (24). The compound (24) can be produced by, for example,reacting the compound (23) with zinc powder (Zn powder) in a solvent inthe presence of acetic acid. Examples of the solvent used may includemethanol, ethanol, water, tetrahydrofuran, mixed solvents of them andthe like. The reaction temperature can usually be performed at 0° C. tothe reflux temperature of the solvent and is performed preferably at 10°C. to 40° C. The reaction time varies depending on the startingmaterials used, the solvent used, the reaction temperature or the like,but is usually 30 minutes to 3 days.

Step 6-4

This step is a step of hydrolyzing the ester moiety of the compound (24)to produce the compound (1d). The compound (1d) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compound (1e)

The compound (1) when R¹ is a —O—C₁ to C₆ alkyl group (this compound mayhereinafter be referred to as the compound (1e)) can be produced fromthe compound (14) in accordance with any of methods described in scheme7, methods similar thereto, methods described in other literatures, andmethods similar thereto.

In the above formulas, Ar², R², R³, R^(a), Q¹, and W are as describedabove, and each carbon atom marked with an asterisk is an asymmetriccarbon atom.

Step 7-1

This step is a step of producing the compound (25) from the compound(14). The compound (25) can be produced by, for example, reacting thecompound (14) with zinc powder in a solvent in the presence of ammoniumchloride. Examples of the solvent used may include methanol, ethanol,water, tetrahydrofuran, mixed solvents of them and the like. Thereaction temperature can usually be performed at 0° C. to the refluxtemperature of the solvent and is performed preferably at 10° C. to 40°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually10 minutes to 3 days.

Step 7-2

This step is a step of reacting the compound (25) with the compound (22)to produce the compound (26). The compound (26) can be produced inaccordance with any of the method described in step 6-2 of scheme 6,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 7-3

This step is a step of hydrolyzing the ester moiety of the compound (26)to produce the compound (1e). The compound (1e) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compound (1f)

The compound (1) when R¹ is a hydrogen atom and Ar² is a grouprepresented by A7) (this compound may hereinafter be referred to as thecompound (1f)) can be produced from the compound (27) in accordance withany of methods described in scheme 8, methods similar thereto, methodsdescribed in other literatures, and methods similar thereto.

In the above formulas, R², R³, R⁷, R⁸, Q¹, and m are as described above,and each carbon atom marked with an asterisk is an asymmetric carbonatom.

Step 8-1

This step is a step of deprotecting the tert-butyldimethylsilyl (TBS)group in the compound (27) to produce the compound (28). The compound(28) can be produced by, for example, reacting the compound (27) with anaqueous hydrogen chloride solution in a solvent. Examples of the solventused may include tetrahydrofuran, water, mixed solvents of them and thelike. The reaction temperature can usually be performed at 0° C. to thereflux temperature of the solvent and is performed preferably at 20° C.to 40° C. The reaction time varies depending on the starting materialsused, the solvent used, the reaction temperature or the like, but isusually 30 minutes to 3 days.

The compound (27) used in this step can be produced in accordance withany of methods described in scheme 3 or 4, methods similar thereto,methods described in other literatures, and methods similar thereto.

Step 8-2

This step is a step of reducing the hydroxy group in the compound (28)to produce the compound (29). The compound (29) can be produced by, forexample, hydrogenating the compound (28) in a solvent in the presence ofa catalyst such as 10% palladium on carbon (10% Pd—C) Examples of thesolvent used may include methanol, ethanol, dichloromethane,tetrahydrofuran, ethyl acetate, acetic acid, mixed solvents of them andthe like. The reaction temperature can usually be performed at 0° C. tothe reflux temperature of the solvent and is performed preferably at 20°C. to 40° C. The reaction time varies depending on the startingmaterials used, the solvent used, the reaction temperature or the like,but is usually 30 minutes to 3 days.

Step 8-3

This step is a step of hydrolyzing the ester moiety of the compound (29)to produce the compound (1f). The compound (1f) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compounds (3c) to (3e)

The compound (3) when R¹ is a C₁ to C₆ alkyl group optionally havingsubstituent(s) (these compounds may hereinafter be referred to as thecompound (3c), the compound (3d), and the compound (3e)) can be producedfrom the compound (3a) in accordance with any of methods described inscheme 9, methods similar thereto, methods described in otherliteratures, and methods similar thereto.

In the above formulas, Ar², R², R³, R^(a), Q¹, and W are as describedabove, R^(b) and R^(c) are each independently a hydrogen atom or a C₁₋₆alkyl group, Y¹ is a C₁₋₃ alkylene, Y² is a single bond or a C₁₋₃alkylene group, and each carbon atom marked with an asterisk is anasymmetric carbon atom.

Step 9-1

This step is a step of protecting the amino group in the compound (3a)with a tert-butoxycarbonyl (Boc) group to produce the compound (30). Thecompound (30) can be produced by, for example, reacting the compound(3a) with di-tert-butyl dicarbonate ((Boc)₂O) in a solvent in thepresence or absence of a base. Examples of the solvent used may includewater, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide,1,4-dioxane, acetonitrile, mixed solvents of them and the like. Examplesof the base used may include trimethylamine, triethylamine,N-methylmorpholine and the like. The reaction temperature can usually beperformed at 0° C. to the reflux temperature of the solvent and isperformed preferably at 10° C. to 60° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

Step 9-2

This step is a step of reacting the compound (30) with the compound (22)to produce the compound (31). The compound (31) can be produced by, forexample, reacting the compound (30) with the compound (22) in a solventin the presence of a base. Examples of the solvent used may includetetrahydrofuran, N,N-dimethylformamide, mixed solvents of them and thelike. Examples of the base used may include lithium hydride, sodiumhydride, potassium tert-butoxide and the like. The reaction temperaturecan usually be performed at −10° C. to the reflux temperature of thesolvent and is performed preferably at 0° C. to 60° C. The reaction timevaries depending on the starting materials used, the solvent used, thereaction temperature or the like, but is usually 30 minutes to 3 days.

Further, the compound (22) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto.

Step 9-3

This step is a step of deprotecting the tert-butoxycarbonyl (Boc) groupin the compound (31) to produce the compound (3c). The compound (3c) canbe produced in accordance with any of the method described in step 5-4of scheme 5, methods similar thereto, methods described in otherliteratures, and methods similar thereto.

Step 9-4

This step is a step of reacting the compound (30) with the compound (32)to produce the compound (33). The compound (33) can be produced inaccordance with any of the method described in step 9-2 of scheme 9,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Further, the compound (32) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto.

Step 9-5

This step is a step of deprotecting the TBS and Boc groups in thecompound (33) to produce the compound (3d). The compound (3d) can beproduced by, for example, reacting the compound (33) with an acid suchas trifluoroacetic acid (TFA) or hydrogen chloride in a water-containingsolvent. Examples of the solvent used may include mixtures of water withmethanol, ethanol, dioxane, and so on. The reaction temperature canusually be performed at −10° C. to the reflux temperature of the solventand is performed preferably at 0° C. to 60° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

Step 9-6

This step is a step of reacting the compound (30) with the compound (34)to produce the compound (35). The compound (35) can be produced inaccordance with any of the method described in step 9-2 of scheme 9,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Further, the compound (34) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto.

Step 9-7

This step is a step of deprotecting the Boc group in the compound (35)to produce the compound (3e). The compound (3e) can be produced inaccordance with any of the method described in step 5-4 of scheme 5,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Alternative Synthesis of Compounds (3c) and (3d)

The compounds (3c) and (3d) can be produced from the compound (5) inaccordance with any of methods described in scheme 10, methods similarthereto, methods described in other literatures, and methods similarthereto.

In the above formulas, Ar², R², R³, R^(a), W, and Y¹ are as describedabove, and each carbon atom marked with an asterisk is an asymmetriccarbon atom.

Step 10-1

This step is a step of reacting the compound (5) with the compound (22)to produce the compound (36). The compound (36) can be produced inaccordance with any of the method described in step 9-2 of scheme 9,methods similar thereto, methods described in other literatures, andmethods similar thereto.

The compound (22) used in this step may be a commercially available, orcan also be produced in accordance with any of methods described inother literatures, and methods similar thereto.

Step 10-2

This step is a step of deprotecting the benzyloxycarbonyl (Cbz) group inthe compound (36) to produce the compound (3c). The compound (3c) can beproduced in accordance with any of the method described in step 2-4 ofscheme 2, methods similar thereto, methods described in otherliteratures, and methods similar thereto.

Step 10-3

This step is a step of reacting the compound (5) with the compound (32)to produce the compound (37). The compound (37) can be produced inaccordance with any of the method described in step 9-2 of scheme 9,methods similar thereto, methods described in other literatures, andmethods similar thereto.

The compound (32) used in this step may be a commercially available, orcan also be produced in accordance with any of methods described inother literatures, and methods similar thereto.

Step 10-4

This step is a step of deprotecting the TBS group in the compound (37)to produce the compound (38). The compound (38) can be produced by, forexample, reacting the compound (37) with tetrabutylammonium fluoride(TBAF) in a solvent. Examples of the solvent used may includetetrahydrofuran, N,N-dimethylformamide, mixed solvents of them and thelike. The reaction temperature can usually be performed at 0° C. to thereflux temperature of the solvent and is performed preferably at 10° C.to 40° C. The reaction time varies depending on the starting materialsused, the solvent used, the reaction temperature or the like, but isusually 30 minutes to 3 days.

Step 10-5

This step is a step of deprotecting the Cbz group in the compound (38)to produce the compound (3d). The compound (3d) can be produced inaccordance with any of the method described in step 2-4 of scheme 2,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compounds (3f) to (3g)

The compounds represented by the following formula (3f) (the compoundmay hereinafter be referred to as the compound (3f)) and represented bythe following formula (3g) (the compound may hereinafter be referred toas the compound (3g)) among the compound (3) can be produced from thecompound (39) in accordance with any of methods described in scheme 11,methods similar thereto, methods described in other literatures, andmethods similar thereto.

In the above formulas, Ar², R², R³, R^(a), Q¹, and W are as describedabove, and each carbon atom marked with an asterisk is an asymmetriccarbon atom.

Step 11-1

This step is a step of reacting the compound (39) with the compound (22)to produce the compound (40). The compound (40) can be produced by, forexample, reacting the compound (39) with the compound (22) in a solventin the presence of a base. Examples of the solvent used may includetetrahydrofuran and the like. Examples of the base used may includeorganolithiums such as lithium diisopropylamide (LDA), lithiumhexamethyl disilazide (LHMDS) and the like. The reaction temperature canusually be performed at −78° C. to the reflux temperature of the solventand is performed preferably at −78° C. to 30° C. The reaction timevaries depending on the starting materials used, the solvent used, thereaction temperature or the like, but is usually 30 minutes to 3 days.

The compound (39) used in this step can be produced in accordance withany of the method described in step 9-2 of scheme 9, methods similarthereto, methods described in other literatures, and methods similarthereto.

Further, the compound (22) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto.

Step 11-2

This step is a step of reducing the ester moiety of the compound (40) toproduce the compound (41). The compound (41) can be produced by, forexample, reacting the compound (40) with a reducing agent such aslithium borohydride (LiBH₄), lithium aluminum hydride (LiAlH₄),diisobutylaluminium hydride (DIBAL) and the like in a solvent. Examplesof the solvent used may include tetrahydrofuran and the like. Thereaction temperature can usually be performed at −20° C. to the refluxtemperature of the solvent and is performed preferably at 0° C. to 30°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually30 minutes to 3 days.

Step 11-3

This step is a step of deprotecting the Boc group in the compound (41)to produce the compound (3f). The compound (3f) can be produced inaccordance with any of the method described in step 5-4 of scheme 5,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 11-4

This step is a step of deprotecting the Boc group in the compound (40)to produce the compound (3g). The compound (3g) can be produced inaccordance with any of the method described in step 5-4 of scheme 5,methods similar thereto, methods described in other literatures, andmethods similar thereto.

The compound (3g) can be produced from the compound (42) in accordancewith any of methods described in scheme 12, methods similar thereto,methods described in other literatures, and methods similar thereto.

In the above formulas, Ar², R², R³, R^(a), and Q¹ are as describedabove, and each carbon atom marked with an asterisk is an asymmetriccarbon atom.

Step 12-1

This step is a step of reacting the compound (22) with the compound (42)to produce the compound (43). The compound (43) can be produced inaccordance with any of the method described in step 11-1 of scheme 11,methods similar thereto, methods described in other literatures, andmethods similar thereto.

The compound (42) used in this step can be produced in accordance withany of the method described in step 10-1 of scheme 10, methods similarthereto, methods described in other literatures, and methods similarthereto.

Step 12-2

This step is a step of deprotecting the Cbz group in the compound (43)to produce the compound (3g). The compound (3g) can be produced inaccordance with any of the method described in step 2-4 of scheme 2,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compounds (3h) and (3i)

The compounds represented by the following formula (3h) (the compoundmay hereinafter be referred to as the compound (3h)) and represented bythe following formula (3i) (the compound may hereinafter be referred toas the compound (3i)) among the compound (3) can be produced from thecompound (5) in accordance with any of methods described in scheme 13,methods similar thereto, methods described in other literatures, andmethods similar thereto.

In the above formulas, Ar², R², R³, R^(a), R^(b), R, Q¹, W, and Y² areas described above, and each carbon atom marked with an asterisk is anasymmetric carbon atom.

Step 13-1

This step is a step of reacting the compound (5) with the compound (34)to produce the compound (44). The compound (44) can be produced inaccordance with any of the method described in step 9-2 of scheme 9,methods similar thereto, methods described in other literatures, andmethods similar thereto.

The compound (34) used in this step may be a commercially available, orcan also be produced in accordance with any of methods described inother literatures, and methods similar thereto.

Step 13-2

This step is a step of hydrolyzing the ester moiety of the compound (44)to produce the compound (45). The compound (45) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 13-3

This step is a step of reacting the compound (45) with the compound (46)to produce the compound (47). The compound (47) can be produced by, forexample, reacting the compound (45) with the compound (46) in a solventin the presence or absence of a base and in the presence of a condensingagent. Examples of the solvent used may include N,N-dimethylformamide,dichloromethane, 1,4-dioxane, tetrahydrofuran, mixed solvents of themand the like. Examples of the condensing agent used may include1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),dicyclohexylcarbodiimide (DCC),2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU) and the like. If required,N,N-dimethylamino pyridine, pyridine, 1-hydroxybenzotriazole (HOBT) andthe like can be used as a reaction promotor. The reaction temperaturecan usually be performed at 0° C. to the reflux temperature of thesolvent and is performed preferably at 0° C. to 30° C. Examples of theusable base may include potassium carbonate, sodium carbonate,triethylamine, N,N-diisopropylethylamine and the like. The reaction timevaries depending on the starting materials used, the solvent used, thereaction temperature or the like, but is usually 30 minutes to 3 days.

The compound (46) used in this step may be a commercially available, orcan also be produced in accordance with any of methods described inother literatures, and methods similar thereto.

Step 13-4

This step is a step of producing the compound (48) from the compound(47). The compound (48) can be produced by, for example, reacting thecompound (47) with triphenylphosphine, triethylamine, and1,1,1,2,2,2-hexachloroethane in a solvent. Examples of the solvent usedmay include dichloromethane and the like. The reaction temperature canusually be performed at −78° C. to the reflux temperature of the solventand is performed preferably at 0° C. to 30° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

Step 13-5

This step is a step of deprotecting the Cbz group in the compound (48)to produce the compound (3h). The compound (3h) can be produced inaccordance with any of the method described in step 2-4 of scheme 2,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 13-6

This step is a step of reacting the compound (45) with the compound (49)to produce the compound (50). The compound (50) can be produced inaccordance with any of the method described in step 13-3 of scheme 13,methods similar thereto, methods described in other literatures, andmethods similar thereto.

The compound (49) used in this step may be a commercially available, orcan also be produced in accordance with any of methods described inother literatures, and methods similar thereto.

Step 13-7

This step is a step of oxidizing the alcohol moiety of the compound (50)to a ketone to produce the compound (51). The compound (51) can beproduced by, for example, reacting the compound (50) with an oxidizersuch as 2-iodoxybenzoic acid in a solvent. Examples of the solvent usedmay include dimethyl sulfoxide and the like. The reaction temperaturecan usually be performed at 0° C. to the reflux temperature of thesolvent and is performed preferably at 10° C. to 30° C. The reactiontime varies depending on the starting materials used, the solvent used,the reaction temperature or the like, but is usually 30 minutes to 3days.

Step 13-8

This step is a step of producing the compound (52) from the compound(51). The compound (52) can be produced by, for example, reacting thecompound (51) with triphenylphosphine and triethylamine in a solvent.Examples of the solvent used may include carbon tetrachloride and thelike. The reaction temperature can usually be performed at 0° C. to thereflux temperature of the solvent and is performed preferably at 50° C.to 90° C. The reaction time varies depending on the starting materialsused, the solvent used, the reaction temperature or the like, but isusually 30 minutes to 3 days.

Step 13-9

This step is a step of deprotecting the Cbz group in the compound (52)to produce the compound (3i). The compound (3i) can be produced inaccordance with any of the method described in step 2-4 of scheme 2,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compound (3j)

The compound represented by the following formula (3j) (the compound mayhereinafter be referred to as the compound (3j)) among the compound (3)can be produced from the compound (53) in accordance with any of methodsdescribed in scheme 14, methods similar thereto, methods described inother literatures, and methods similar thereto.

In the above formulas, Ar², R², R³, and R^(a) are as described above,and each carbon atom marked with an asterisk is an asymmetric carbonatom.

Step 14-1

This step is a step of converting the sulfanyl group in the compound(53) to a sulfonyl group to produce the compound (54). The compound (54)can be produced by, for example, treating the compound (53) with anoxidizer such as meta-chloroperoxybenzoic acid (m-CPBA) in a solvent.Examples of the solvent used may include dichloromethane, acetonitrile,tetrahydrofuran, mixed solvents of them and the like. The amount of theoxidizer used is usually about 2 to 5 molar equivalents with respect to1 mole of the compound (53). The reaction temperature can usually beperformed at 0° C. to the reflux temperature of the solvent and isperformed preferably at 0° C. to 30° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

The compound (53) used in this step can be produced in accordance withany of the method described in step 10-1 of scheme 10, methods similarthereto, methods described in other literatures, and methods similarthereto.

Step 14-2

This step is a step of deprotecting the Cbz group in the compound (54)to produce the compound (3j). The compound (3j) can be produced inaccordance with any of the method described in step 2-4 of scheme 2,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of compounds (Ic), (Id), and (Ie)

The compounds represented by the following formulas (Ic), (Id), and (Ie)(the compounds may hereinafter be referred to as the compounds (Ic),(Id), and (Ie)) among the compound (I) can be produced from the compound(3e) in accordance with any of methods described in scheme 15, methodssimilar thereto, methods described in other literatures, and methodssimilar thereto.

In the above formulas, Ar¹, Ar², R², R³, R^(b), R^(c), Y², and Q¹ are asdescribed above, Q² and Q³ are each independently a hydrogen atom or aC₁₋₆ alkyl group optionally having substituent(s) or Q² and Q³ togetherform an alkylene group, and each carbon atom marked with an asterisk isan asymmetric carbon atom.

Step 15-1

This step is a step of reacting the compound (3e) with the compound (4)to produce the compound (Ic). The compound (Ic) can be produced inaccordance with any of the method described in step 1-2 of scheme 1,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 15-2

This step is a step of hydrolyzing the ester moiety of the compound (Ic)to produce the compound (Id). The compound (Id) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 15-3

This step is a step of reacting the compound (Id) with the compound (55)to produce the compound (Ie). The compound (Ie) can be produced inaccordance with any of the method described in step 13-3 of scheme 13,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Further, the compound (55) used in this step may be a commerciallyavailable, or can be produced in accordance with any of methodsdescribed in other literatures, and methods similar thereto.

Synthesis of Compounds (If), (Ig), (Ih), and (Ii)

The compounds represented by the following formulas (If), (Ig), (Ih),and (Ii) (the compounds may hereinafter be referred to as the compounds(If), (Ig), (Ih), and (Ii)) among the compound (I) of the embodiment canbe produced from the compound (56) in accordance with any of methodsdescribed in scheme 16, methods similar thereto, methods described inother literatures, and methods similar thereto.

In the above formulas, Ar¹, R², R³, R⁷, R⁸, Q¹, Q², and Q³ are asdescribed above, and each carbon atom marked with an asterisk is anasymmetric carbon atom.

Step 16-1

This step is a step of protecting the phenolic hydroxy group in thecompound (56) with a benzyl (Bn) group to produce the compound (57). Thecompound (57) can be produced by, for example, reacting the compound(56) with benzyl bromide in a solvent in the presence of a base.Examples of the solvent used may include tetrahydrofuran,N,N-dimethylformamide, mixed solvents of them and the like. Examples ofthe base used may include sodium carbonate, potassium carbonate, cesiumcarbonate and the like. The reaction temperature can usually beperformed at 0° C. to the reflux temperature of the solvent and isperformed preferably at 10° C. to 40° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

The compound (56) used in this step can be produced in accordance withany of methods described in scheme 3 or 4, methods similar thereto,methods described in other literatures, and methods similar thereto.

Step 16-2

This step is a step of hydrolyzing the ester moiety of the compound (57)to produce the compound (58). The compound (58) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 16-3

This step is a step of producing the compound (59) from the compound(58). The compound (59) can be produced in accordance with any of themethod described in step 1-1 of scheme 1, methods similar thereto,methods described in other literatures, and methods similar thereto.

Step 16-4

This step is a step of deprotecting the Bn group in the compound (59) toproduce the compound (If). The compound (If) can be produced by, forexample, hydrogenating the compound (59) in a solvent in the presence ofa catalyst such as 10% palladium on carbon (10% Pd—C) and the like.Examples of the solvent used may include methanol, ethanol,dichloromethane, tetrahydrofuran, ethyl acetate, mixed solvents of themand the like. The reaction temperature can usually be performed at 0° C.to the reflux temperature of the solvent and is performed preferably at10° C. to 40° C. The reaction time varies depending on the startingmaterials used, the solvent used, the reaction temperature or the like,but is usually 30 minutes to 3 days.

Step 16-5

This step is a step of trifluoromethane-sulfonylating the hydroxy groupin the compound (If) to produce the compound (60). The compound (60) canbe produced by, for example, reacting the compound (If) with atrifluoromethane-sulfonylation agent in a solvent in the presence of abase. Examples of the solvent used may include dichloromethane,1,2-dichloroethane, pyridine, tetrahydrofuran, N,N-dimethylformamide,1,4-dioxane, acetonitrile, diethyl ether, mixed solvents of them and thelike. Examples of the trifluoromethane-sulfonylation agent may includeN-phenyl bis(trifluoromethanesulfonimide), trifluoromethanesulfonicanhydride and the like. Examples of the base used may include potassiumcarbonate, sodium carbonate, sodium hydride, potassium phosphate,N,N-diisopropylethylamine, triethylamine, 2,6-lutidine and the like. Thereaction temperature can usually be performed at −78° C. to the refluxtemperature of the solvent and is performed preferably at −20° C. to 30°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually30 minutes to 3 days.

Step 16-6

This step is a step of producing the compound (Ig) from the compound(60). The compound (Ig) can be produced by, for example, reacting thecompound (60) with the compound (55) in a solvent in the presence ofacetonitrile, cesium carbonate,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), palladiumacetate(II), and molybdenum hexacarbonyl (Mo(CO)₆). Examples of thesolvent used may include toluene and the like. The reaction temperaturecan usually be performed at 0° C. to the reflux temperature of thesolvent and is performed preferably at 50° C. to 80° C. The reactiontime varies depending on the starting materials used, the solvent used,the reaction temperature or the like, but is usually 30 minutes to 3days.

Step 16-7

This step is a step of producing the compound (Ih) from the compound(60). The compound (Ih) can be produced by, for example, reacting thecompound (60) with zinc cyanide (Zn(CN)₂) in a solvent using a palladiumreagent as a catalyst. Examples of the solvent used may include1,4-dioxane, toluene, N,N-dimethylformamide, mixed solvents of them andthe like. Examples of the palladium reagent used may includetetrakis(triphenylphosphine) palladium (0) (Pd(PPh₃)₄) and the like. Thereaction temperature can usually be performed at 20° C. to the refluxtemperature of the solvent and is performed preferably at 60° C. to 100°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually30 minutes to 3 days.

Step 16-8

This step is a step of hydrolyzing the cyano group in the compound (Ih)to an amido group to produce the compound (Ii). The compound (Ii) can beproduced by, for example, reacting the compound (Ih) in a solvent in thepresence of a base. Examples of the solvent used may include water,methanol, ethanol, propanol, 2-propanol, butanol, tetrahydrofuran, mixedsolvents of them and the like. Examples of the base used may includelithium hydroxide, sodium hydroxide, potassium hydroxide and the like.The reaction temperature can usually be performed at 0° C. to the reflux temperature of the solvent and is performed preferably at 60° C. to100° C. The reaction time varies depending on the starting materialsused, the solvent used, the reaction temperature or the like, but isusually 30 minutes to 3 days.

Synthesis of Compounds (Ij), (Ik), and Compound (Il)

The compound represented by the following formula (Ij) (the compound mayhereinafter be referred to as the compound (Ij)) among the compound (I)of the embodiment can be produced in accordance with any of methodsdescribed in scheme 1, methods similar thereto, methods described inother literatures, and methods similar thereto.

Furthermore, the compounds represented by the following formulas (Ik)and (Il) (the compounds may hereinafter be referred to as the compounds(Ik) and (Il)) among the compound (I) of the embodiment can be producedfrom the compound (Ij) in accordance with any of methods described inscheme 17, methods similar thereto, methods described in otherliteratures, and methods similar thereto.

In the above formulas, Ar¹, R¹, R², R³, R⁷, and R⁸ are as describedabove, R^(e) is a C₁₋₆ alkyl group, and each carbon atom marked with anasterisk is an asymmetric carbon atom.

Step 17-1

This step is a step of converting the sulfanyl group in the compound(Ij) to a sulfinyl group to produce the compound (Ik). The compound (Ik)can be produced by, for example, treating the compound (Ij) with anoxidizer such as meta-chloroperoxybenzoic acid (m-CPBA) in a solvent.Examples of the solvent used may include dichloromethane, acetonitrile,tetrahydrofuran, mixed solvents of them and the like. The amount of theoxidizer used is usually about 1 to 2 molar equivalents with respect to1 mole of the compound (Ij). The reaction temperature can usually beperformed at 0° C. to the reflux temperature of the solvent and isperformed preferably at 0° C. to 30° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

Step 17-2

This step is a step of converting the sulfanyl group in the compound(Ij) to a sulfonyl group to produce the compound (Il). The compound (Il)can be produced by, for example, treating the compound (Ij) with anoxidizer such as meta-chloroperoxybenzoic acid (m-CPBA) in a solvent.Examples of the solvent used may include dichloromethane, acetonitrile,tetrahydrofuran, mixed solvents of them and the like. The amount of theoxidizer used is usually about 2 to 5 molar equivalents with respect to1 mole of the compound (Ij). The reaction temperature can usually beperformed at 0° C. to the reflux temperature of the solvent and isperformed preferably at 0° C. to 30° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

Synthesis of Compounds (Im), (In), Compound (Io), and Compound (Ip)

The compound represented by the following formula (Im) (the compound mayhereinafter be referred to as the compound (Im)) among the compound (I)of the embodiment can be produced in accordance with any of methodsdescribed in scheme 1, methods similar thereto, methods described inother literatures, and methods similar thereto.

Furthermore, the compounds represented by the following formulas (In),(Io) and (Ip) (the compounds may hereinafter be referred to as thecompounds (In), (Io) and (Ip)) among the compound (I) of the embodimentcan be produced from the compound (Im) in accordance with any of methodsdescribed in scheme 18, methods similar thereto, methods described inother literatures, and methods similar thereto.

In the above formulas, Ar², R¹, R², R³, R¹³, Q¹, Q², and Q³ are asdescribed above, and each carbon atom marked with an asterisk is anasymmetric carbon atom.

Step 18-1

This step is a step of reducing the ester moiety of the compound (Im) toproduce the compound (In). The compound (In) can be produced by, forexample, treating the compound (Im) with a reducing agent such asdiisobutylaluminum hydride in a solvent. Examples of the solvent usedmay include dichloromethane, tetrahydrofuran, toluene, mixed solvents ofthem and the like. The reaction temperature can usually be performed at0° C. to the reflux temperature of the solvent and is performedpreferably at 0° C. to 30° C. The reaction time varies depending on thestarting materials used, the solvent used, the reaction temperature orthe like, but is usually 30 minutes to 3 days.

Step 18-2

This step is a step of hydrolyzing the ester moiety of the compound (Im)to produce the compound (Io). The compound (Io) can be produced inaccordance with any of the method described in step 3-4 of scheme 3,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Step 18-3

This step is a step of reacting the compound (Io) with the compound (55)to produce the compound (Ip). The compound (Ip) can be produced inaccordance with any of the method described in step 13-3 of scheme 13,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compound (Iq)

The compound represented by the following formula (Iq) (the compound mayhereinafter be referred to as the compound (Iq)) among the compound (I)of the embodiment can be produced from the compound (61) in accordancewith any of method described in scheme 19, methods similar thereto,methods described in other literatures, and methods similar thereto.

In the above formulas, Ar¹, Ar², R², and R³ are as described above,R^(f) is a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, or a TBSO group, andeach carbon atom marked with an asterisk is an asymmetric carbon atom.

Step 19-1

This step is a step of producing the compound (Iq) from the compound(61). The compound (Iq) can be produced in accordance with any of themethod described in step 1-2 of scheme 1, methods similar thereto,methods described in other literatures, and methods similar thereto.

The compound (61) can be produced from the compound (5) in accordancewith any of methods described in scheme 20, methods similar thereto,methods described in other literatures, and methods similar thereto.

In the above formulas, Ar², R², R³, and R^(f) are as described above,and each carbon atom marked with an asterisk is an asymmetric carbonatom.

Step 20-1

This step is a step of producing the compound (62) from the compound(5). The compound (62) can be produced by, for example, reacting thecompound (5) with triethyloxonium hexafluorophosphate (Et₃OPF₆) in asolvent. Examples of the solvent used may include dichloromethane andthe like. The reaction temperature can usually be performed at 0° C. tothe ref lux temperature of the solvent and is performed preferably at10° C. to 40° C. The reaction time varies depending on the startingmaterials used, the solvent used, the reaction temperature or the like,but is usually 30 minutes to 3 days.

Step 20-2

This step is a step of reacting the compound (62) with the compound (63)to produce the compound (64). The compound (64) can be produced by, forexample, reacting the compound (62) with the compound (63) in a solventin the presence or absence of an acid or a base. Examples of the solventused may include methanol, ethanol, toluene, tetrahydrofuran,acetonitrile, dioxane, mixed solvents of them and the like. Examples ofthe acid that may be used may include hydrogen chloride, ammoniumchloride and the like. Examples of the base that may be used may includetrimethylamine, triethylamine, N-methylmorpholine and the like. Thereaction temperature can usually be performed at 0° C. to the refluxtemperature of the solvent and is performed preferably at 0° C. to 50°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually10 minutes to 3 days.

Further, the compound (63) may be a commercially available, or can beproduced in accordance with any of methods described in otherliteratures, and methods similar thereto.

Step 20-3

This step is a step of deprotecting the Cbz group in the compound (64)to produce the compound (61). The compound (61) can be produced inaccordance with any of the method described in step 2-4 of scheme 2,methods similar thereto, methods described in other literatures, andmethods similar thereto.

Synthesis of Compound (Ir)

The compound (Ir) can be produced from the compound (65) in accordancewith any of methods described in scheme 21, methods similar thereto,methods described in other literatures, and methods similar thereto.

In the above formulas, Ar¹, Ar², R², and R³ are as described above, andeach carbon atom marked with an asterisk is an asymmetric carbon atom.

Step 21-1

This step is a step of deprotecting the TBS group in the compound (65)to produce the compound (Ir). The compound (Ir) can be produced by, forexample, reacting the compound (65) with an acid such as trifluoroaceticacid (TFA) or hydrogen chloride in a solvent mixture of water-dioxane.

The reaction temperature can usually be performed at −20° C. to thereflux temperature of the solvent and is performed preferably at 0° C.to 30° C. The reaction time varies depending on the starting materialsused, the solvent used, the reaction temperature or the like, but isusually 30 minutes to 3 days.

The compound (65) used in this step can be produced in accordance withany of methods described in scheme 19, methods similar thereto, methodsdescribed in other literatures, and methods similar thereto.

Step 22 Synthesis of Compounds (Is) and (It)

The compound represented by the following formula (Is) (the compound mayhereinafter be referred to as the compound (Is)) among the compound (I)of the embodiment can be produced in accordance with any of methodsdescribed in scheme 1, methods similar thereto, methods described inother literatures, and methods similar thereto.

Furthermore, the compound represented by the following formula (It) (thecompound may hereinafter be referred to as the compound (It)) among thecompound (I) of the embodiment can be produced, for example, from thecompound (Is) in accordance with any of methods described in scheme 22,methods similar thereto, methods described in other literatures, andmethods similar thereto.

In the above formulas, Ar², R¹, R², R³, and R¹³ are as described above,X is a halogen atom, and each carbon atom marked with an asterisk is anasymmetric carbon atom.

Step 22-1

This step is a step of reacting the compound (Is) withtrimethylsilylacetylene (66) to produce the compound (67). The compound(67) can be produced by, for example, reacting the compound (Is) withtrimethylsilylacetylene (66) in a solvent in the presence ofdichlorobis(triphenylphosphine)palladium(II), copper(I) iodide, andtriethylamine. Examples of the solvent used may includeN,N-dimethylformamide and the like. The reaction temperature can usuallybe performed at 0° C. to the reflux temperature of the solvent and isperformed preferably at 40° C. to 60° C. The reaction time variesdepending on the starting materials used, the solvent used, the reactiontemperature or the like, but is usually 30 minutes to 3 days.

Step 22-2

This step is a step of deprotecting the TMS group in the compound (67)to produce the compound (It). The compound (It) can be produced by, forexample, reacting the compound (67) with potassium carbonate in asolvent. Examples of the solvent used may include methanol and the like.The reaction temperature can usually be performed at 0° C. to the refluxtemperature of the solvent and is performed preferably at 20° C. to 40°C. The reaction time varies depending on the starting materials used,the solvent used, the reaction temperature or the like, but is usually30 minutes to 3 days.

Synthesis of Compound (Iu)

The compound represented by the following formula (Iu) (the compound mayhereinafter be referred to as the compound (Iu)) among the compound (I)of the embodiment can be produced, for example, from the compound (68)in accordance with any of method described in scheme 23, methods similarthereto, methods described in other literatures, and methods similarthereto.

In the above formulas, Ar¹, R¹, R², R³, R⁷, R⁸, and R^(a) are asdescribed above, and each carbon atom marked with an asterisk is anasymmetric carbon atom.

Step 23-1

This step is a step of deprotecting the Boc group in the compound (68)to produce the compound (Iu). The compound (Iu) can be produced inaccordance with any of the method described in step 5-4 of scheme 5,methods similar thereto, methods described in other literatures, andmethods similar thereto.

The compound (68) used in this step can be produced in accordance withany of methods described in scheme 1, methods similar thereto, methodsdescribed in other literatures, and methods similar thereto.

Synthesis of Compounds (Iv) and (Iw)

The compound represented by the following formula (Iv) (the compound mayhereinafter be referred to as the compound (Iv)) among the compound (I)of the embodiment can be produced in accordance with any of methodsdescribed in scheme 1, methods similar thereto, methods described inother literatures, and methods similar thereto.

Furthermore, the compound represented by the following formula (Iw) (thecompound may hereinafter be referred to as the compound (Iw)) among thecompound (I) of the embodiment can be produced, for example, from thecompound (Iv) in accordance with any of methods described in scheme 24,methods similar thereto, methods described in other literatures, andmethods similar thereto.

In the above formulas, Ar¹, R¹, R², R³, R⁷, R⁸, and m are as describedabove, and each carbon atom marked with an asterisk is an asymmetriccarbon atom.

Step 24-1

This step is a step of converting the hydroxy group in the compound (Iv)to a ketone to produce the compound (Iw). The compound (Iw) can beproduced by, for example, treating the compound (Iv) with an oxidizersuch as Dess-Martin periodinane in a solvent. Examples of the solventused may include dichloromethane, acetonitrile, mixed solvents of themand the like. The amount of the oxidizer used is usually about 1 to 2molar equivalents with respect to 1 mole of the compound. The reactiontemperature can usually be performed at 0° C. to the reflux temperatureof the solvent and is performed preferably at 20° C. to 30° C. Thereaction time varies depending on the starting materials used, thesolvent used, the reaction temperature or the like, but is usually 30minutes to 3 days.

Step 25 Synthesis of Compound (Ix)

The compound represented by the following formula (Ix) (the compound mayhereinafter be referred to as the compound (Ix)) among the compound (I)of the embodiment can be produced, for example, from the compound (69)in accordance with any of method described in scheme 25, methods similarthereto, methods described in other literatures, and methods similarthereto.

In the above formulas, Ar¹, R¹, R², R³, R⁷, R⁸, and mare as describedabove, and each carbon atom marked with an asterisk is an asymmetriccarbon atom.

Step 25-1

This step is a step of deprotecting the Bn group in the compound (69) toproduce the compound (Ix). The compound (Ix) can be produced by, forexample, hydrogenating the compound (69) in a solvent in the presence ofa catalyst such as 10% palladium on carbon (10% Pd—C). Examples of thesolvent used may include methanol, ethanol, dichloromethane,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, mixed solvents ofthem and the like. Examples of the base used may include triethylamineacetate and the like. The reaction temperature can usually be performedat 0° C. to the reflux temperature of the solvent and is performedpreferably at 20° C. to 40° C. The reaction time varies depending on thestarting materials used, the solvent used, the reaction temperature orthe like, but is usually 30 minutes to 3 days.

The compound (69) used in this step can be produced in accordance withany of methods described in scheme 1, methods similar thereto, methodsdescribed in other literatures, and methods similar thereto.

Synthesis of Compound (Iz)

The compound represented by the following formula (Iy) (the compound mayhereinafter be referred to as the compound (Iy)) among the compound (I)of the embodiment can be produced in accordance with any of methodsdescribed in scheme 1, methods similar thereto, methods described inother literatures, and methods similar thereto.

The compound represented by the following formula (Iz) (the compound mayhereinafter be referred to as the compound (Iz)) among the compound (I)of the embodiment can be produced, for example, from the compound (Iy)in accordance with any of methods described in scheme 26, methodssimilar thereto, methods described in other literatures, and methodssimilar thereto.

In the above formulas, Ar¹, Ar², R², R³, and Y¹ are as described above,and each carbon atom marked with an asterisk is an asymmetric carbonatom.

Step 26-1

This step is a step of producing the compound (Iz) from the compound(Iy). The compound (Iz) can be produced by, for example, reacting thecompound (Iy) with sodium azide in a solvent in the presence oftriethylamine and acetic acid. Examples of the solvent used may includetoluene, N,N-dimethylformamide, isopropanol, water, mixed solvents ofthem and the like. The reaction temperature can usually be performed at0° C. to the reflux temperature of the solvent and is performedpreferably at 100° C. to 130° C. The reaction time varies depending onthe starting materials used, the solvent used, the reaction temperatureor the like, but is usually 30 minutes to 3 days.

A pharmacologically acceptable salt of the compound (I) of the presentembodiment can be produced using the compound (I) of the presentembodiment according to a usual method.

The schemes described above are examples of the method of producing thecompound (I) of the present embodiment or a production intermediatethereof. These schemes can be modified to various schemes that can bereadily understood by a person skilled in the art.

Also, in the case that there is a need of a protective group accordingto the kind of the functional group, an appropriate combination ofintroduction and removal procedures may be performed according to ausual method. For the types of protective groups and introduction andremoval of the protective groups, see, for example, methods described in“Greene's Protective Groups in Organic Synthesis,” Theodra W. Green &Peter G. M. Wuts, ed., fourth edition, Wiley-Interscience, 2006.

The intermediates used for preparation of the compound (I) of thepresent embodiment or a pharmacologically acceptable salt thereof can beisolated/purified, as necessary, by solvent extraction, crystallization,recrystallization, chromatography, or preparative high-performanceliquid chromatography or the like, that is an isolation/purificationmeans well-known to a skilled person in the art.

The term “FPRL1 agonist effect” used in the present embodiment meansthat agonist activity exhibits through the action on formyl peptidereceptor like 1 (FPRL1).

As described above, it is known that LXA4 and peptides reported asendogenous agonists of FPRL1 contribute to resolution of inflammation.

The compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof exhibits superior agonist activity in, forexample, a test of calcium influx into FPRL1-overexpressing cells.Therefore, the compound (I) of the present embodiment or apharmacologically acceptable salt thereof is useful as a therapeutic orprophylactic agent for inflammatory diseases, chronic airway diseases,cancers, septicemia, allergic symptoms, HIV retrovirus infection,circulatory disorders, neuroinflammation, nervous disorders, pains,prion diseases, amyloidosis, immune disorders and the like.

The compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof can also be used to produce pharmaceuticals fortreatment or prevention of inflammatory diseases, chronic airwaydiseases, cancers, septicemia, allergic symptoms, HIV retrovirusinfection, circulatory disorders, neuroinflammation, nervous disorders,pains, prion diseases, amyloidosis, immune disorders and the like.

In addition, pharmaceuticals containing, as an active ingredient, thecompound (I) of the present embodiment or a pharmacologically acceptablesalt thereof can be used as, for example, prophylactic or therapeuticagents for various disease states associated with the FPRL1 receptor(such as Behcet's disease, Sweet disease, systemic lupus erythematosus(SLE), Wegener's granulomatosis, virus infection, diabetes, amputations,cancers, bacterial infection, physical external injuries, physicaldisorders including exposure to radiation, vasoconstriction,anaphylactic reactions, allergic reactions, rhinitis, shocks (endotoxic,hemorrhagic, traumatic, splanchnic ischemia, and circulatory shocks),rheumatoid arthritis, gout, psoriasis, benign prostatic hyperplasia,myocardial ischemia, myocardial infarction, brain injuries, pulmonarydiseases, COPD, COAD, COLD, acute lung injury, acute respiratorydistress syndrome, chronic bronchitis, pulmonary emphysema, asthma(allergic asthma and non-allergic asthma), cystic pulmonary fibrosis,nephropathy, renal glomerular diseases, ulcerative colitis, IBD, Crohn'sdisease, periodontitis, pains, Alzheimer's disease, AIDS, uveiticglaucoma, conjunctivitis, Sjoegren's syndrome, rhinitis and the like).

Pharmaceutical containing the compound (I) of the present embodiment orpharmacologically acceptable salt thereof

A pharmaceutical containing, as an active ingredient, the compound (I)of the present embodiment or a pharmacologically acceptable salt thereofcan have various forms according to the usages. Examples of the formsmay include powders, granules, fine granules, dry syrups, tablets,capsules, injections, liquids, ointments, suppositories, patches,sublingual tablets and the like, which are administered orally orparenterally.

Such a pharmaceutical can be formed as a pharmaceutical compositioncontaining, as an active ingredient, the compound (I) of the presentembodiment or a pharmacologically acceptable salt thereof and apharmacologically acceptable additive using a well-known methodaccording to the form of the pharmaceutical. Examples of the additivecontained in the pharmaceutical composition may include an excipient, adisintegrant, a binder, a lubricant, a diluent, a buffering agent, anisotonizing agent, an antiseptic, a humectant, an emulsifier, adispersant, a stabilizer, a solubilizing agent and the like. Thepharmaceutical composition can be prepared by appropriately mixing thecompound (I) of the present embodiment or a pharmacologically acceptablesalt thereof with an additive or by diluting the compound (I) or apharmacologically acceptable salt thereof with an additive anddissolving it in the additive. When the compound (I) of the presentembodiment or a pharmacologically acceptable salt thereof is used incombination with agents other than the FPRL1 receptor agonist, apharmaceutical composition can be produced by forming active ingredientsof these components into a formulation simultaneously or separately inthe manner described above.

The pharmaceutical according to the present embodiment can besystemically or locally administered orally or parenterally(transnasally, pulmonary, intravenously, intrarectally, hypodermically,intramuscularly, percutaneously and the like).

When a pharmaceutical composition containing, as an active ingredient,the compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof is used for practical treatment, the dose of thecompound (I) of the present embodiment or the pharmacologicallyacceptable salt thereof used as the active ingredient is appropriatelydetermined according to the age, sex, and body weight of the patient,the disease of the patient, the degree of the treatment and the like.For example, in the case of oral administration, it may be appropriatelyadministered to an adult (the body weight is assumed to be 60 kg) at adaily dose within the range of about 0.03 to about 1,000 mg/body in oneportion or several divided portions. The dose per day as an oraladministration is preferably 0.06 to 540 mg/body and more preferably0.18 to 180 mg/body. In the case of parenteral administration, it may beappropriately administered to an adult at a daily dose within the rangeof about 0.01 to about 300 mg/body in one portion or several dividedportions. The dose per day as a parenteral administration is preferably0.01 to 100 mg/body and more preferably 0.06 to 60 mg/body. The dose ofthe compound (I) of the present embodiment or a pharmacologicallyacceptable salt thereof may be reduced according to the dose of agentsother than the FPRL1 receptor agonist.

EXAMPLES

Hereinafter, the present invention will be described in more detail onthe basis of Test Examples, Examples, and Reference Examples. Startingmaterials used in production of the compound (I) include a novelcompound, and therefore Production examples for the starting materialswill be also described as Reference Examples. The present invention isnot limited to compounds described in the following Examples, and may bemodified without departing from the scope of the present invention.

Among symbols used in each Reference Example, each Example, and eachTable, Ref.No. represents Reference Example Number, Ex.No. representsExample Number, P.D. represents physical chemical data, Str. representsa structural formula, and ¹H-NMR represents a proton nuclear magneticresonance spectrum. CDCl₃ represents chloroform-d, and DMSO-d₆represents dimethyl sulfoxide-d₆. MS(ESI⁺) represents mass spectral datameasured by electron-spray ionization. An optical rotation represents aspecific optical rotation, which measured in described solvent atdescribed concentration and temperature using sodium D-line as lightsource.

Wedge-shaped solid line and dashed line in a structural formularepresent relative configuration in an optically active substance, butdo not represent absolute configuration. Thick solid line and dashedline represent relative configuration in a racemate and an opticallyactive substance obtained by resolution of a racemate. A carbon atommarked with “*” represents an asymmetric carbon. A wavy line bond ofcarbon atom marked with “*” represents the presence of a racemate.

Both R* and S* in the name of a compound represent relative stericconfiguration about an asymmetric carbon atom.

When both a substituent and a hydrogen atom are bonded to each of twopositions of a pyrrolidine ring in a structural formula, the relativeconfiguration of the substituents is expressed as cis or trans, and cisor trans is sometimes followed by a hyphen and the name of a compound.

When the pyrrolidine ring is considered as a face, cis means that thetwo adjacent substituents are on the same side, and trans means that thetwo adjacent substituents are on the respective opposite sides.

In order to represent isomers about a double bond and a double bond ofimine in the name of a compound, a cis-isomer is expressed as “Z,” and atrans-isomer is expressed as “E.”

Reference Example 1-1

(E)-2-Fluoro-1-methoxy-4-(2-nitrovinyl)benzene

3-Fluoro-4-methoxybenzaldehyde (500 mg) was dissolved in2-hydroxyethylammonium formate (1.7 g) under an argon atmosphere, andnitromethane (175 μL) was added to produce a reaction solution. Thereaction solution was stirred at room temperature for 9 hours. Water wasadded to the reaction solution, and the precipitated solid was collectedby filtration, and washed with water. The resulting solid was dried toobtain the title compound as a yellow solid (607 mg).

¹H-NMR (400 MHz, CDCl₃) δ3.96 (3H, s), 7.01 (1H, t, J=8.5 Hz), 7.27-7.32(2H, m), 7.48 (1H, d, J=13.3 Hz), 7.92 (1H, d, J=13.3 Hz).

The following Reference Examples 1-2 to 1-27 were obtained using eachcorresponding aromatic aldehyde in the same method as in ReferenceExample 1-1.

The structures and spectral data thereof are shown in Tables 1 to 5.

TABLE 1 Ref. No Str. Chemical name P.D. 1-2

(E)-4-methoxy- 2-methyl-1- (2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 2.47 (3H, s), 3.85 (3H, s), 6.77-6.81 (2H, m), 7.46-7.51 (2H,m), 8.27 (1H, d, J = 13.4 Hz). 1-3

(E)-2-fluoro- 4-methoxy-1- (2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 3.87 (3H, s), 6.71 (1H, dd, J = 12.1, 2.4 Hz), 6.78 (1H, dd, J= 8.5, 2.4 Hz), 7.43 (1H, t, J = 8.5 Hz), 7.66 (1H, d, J = 13.9 Hz),8.02 (1H, d, J = 13.9 Hz). 1-4

(E)-2-chloro- 4-methoxy-1- (2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 3.87 (3H, s), 6.87 (1H, dd, J = 8.5, 2.4 Hz), 7.02 (1H, d, J =2.4 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 13.9 Hz), 8.38 (1H,d, J = 13.9 Hz). 1-5

(E)-1,3-difluoro- 5-methoxy- 2-(2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 3.87 (3H, s), 6.54-6.59 (2H, m), 7.77 (1H, d, J = 13.4 Hz),8.11 (1H, d, J = 13.4 Hz).

TABLE 2 Ref. No Str. Chemical name P.D. 1-6

(E)-1,4-difluoro- 2-methoxy- 5-(2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 3.95 (3H, s), 6.79 (1H, dd, J = 11.0, 6.7 Hz), 7.21 (1H, dd, J= 11.0, 6.7 Hz), 7.61 (1H, d, J = 13.4 Hz), 7.98 (1H, d, J = 13.4 Hz).1-7

(E)-1,3-difluoro- 2-methoxy-5- (2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 4.10 (3H, t, J = 1.8 Hz), 7.07-7.15 (2H, m), 7.46 (1H, d, J =13.4 Hz), 7.84 (1H, d, J = 13.4 Hz). 1-8

(E)-5-(2- nitrovinyl)-2,3- dihydrobenzofuran ¹H-NMR (400 MHz, CDCl₃) δ3.26 (2H, t, J = 8.8 Hz), 4.67 (2H, t, J = 8.8 Hz), 6.84 (1H, d, J = 8.3Hz) 7.35 (1H, d, J = 8.3 Hz), 7.41 (1H, s), 7.51 (1H, d, J = 13.4 Hz),7.97 (1H, d, J = 13.4 Hz). 1-9

(E)-6-fluoro-5- (2-nitrovinyl)-2,3- dihydrobenzofuran ¹H-NMR (400 MHz,CDCl₃) δ 3.23 (2H, t, J = 8.9 Hz), 4.72 (2H, t, J = 8.9 Hz), 6.60 (1H,d, J = 11.6 Hz) 7.30 (1H, d, J = 6.7 Hz), 7.62 (1H, d, J = 13.4 Hz),8.03 (1H, d, J = 13.4 Hz). 1-10

(E)-6-fluoro- 5-(2-nitrovinyl) chromane ¹H-NMR (400 MHz, CDCl₃) δ2.00-2.05 (2H, m), 2.77 (2H, t, J = 6.4 Hz), 4.24 (2H, t, J = 5.5 Hz),6.59 (1H, d, J = 11.6 Hz) 7.17 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J =13.4 Hz), 7.97 (1H, d, J = 13.4 Hz). 1-11

(E)-3-fluoro- 5-methoxy-2- (2-nitrovinyl) pyridine ¹H-NMR (400 MHz,CDCl₃) δ 3.93 (3H, s), 6.98 (1H, dd, J = 11.0, 2.4 Hz) 7.93 (1H, d, J=13.4 Hz), 8.13 (1H, d, J = 13.4 Hz), 8.22 (1H, d, J = 2.4 Hz).

TABLE 3 Ref. No Str. Chemical name P.D. 1-12

(E)-3,5-difluoro- 4-(2-nitrovinyl) phenol ¹H-NMR (400 MHz, CDCl₃) δ6.49-6.55 (2H, m), 7.76 (1H, d, J = 14.1 Hz), 8.10 (1H, d, J = 14.1 Hz).1-13

(E)-methyl(4- (2-nitrovinyl) phenyl)sulfane ¹H-NMR (400 MHz, CDCl₃) δ2.53 (3H, s), 7.27 (2H, d, J = 8.5 Hz), 7.45 (2H, d, J = 8.5 Hz), 7.57(1H, d, J = 13.3 Hz), 7.97 (1H, d, J = 13.3 Hz). 1-14

(E)-2-methoxy- 5-(2-nitrovinyl) thiophene ¹H-NMR (400 MHz, CDCl₃) δ 3.98(3H, s), 6.27 (1H, d, J = 4.2 Hz), 7.19 (1H, d, J = 4.2 Hz), 7.26 (1H,d, J = 13.3 Hz), 8.03 (1H, d, J = 13.3 Hz). 1-15

(E)-1- (difluoromethoxy)- 4-(2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ6.59 (1H, t, J = 73.0 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.53-7.59(3H, m), 7.99 (1H, d, J = 13.3 Hz). 1-16

(E)-5-ethyl-1,3- difluoro-2-(2- nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 1.26 (3H, t, J = 7.6 Hz), 2.69 (2H, q, J = 7.6 Hz), 6.86 (2H,d, J = 9.8 Hz), 7.82 (1H, d, J = 13.4 Hz), 8.13 (1H, d, J = 13.4 Hz).

TABLE 4 Ref. No Str. Chemical name P.D. 1-17

(E)-5- (difluoromethoxy)- 1,3-difluoro-2- (2-nitrovinyl) benzene ¹H-NMR(400 MHz, CDCl₃) δ 6.60 (1H, t, J = 71.5 Hz), 6.82-6.87 (2H, m), 7.81(1H, d, J = 13.9 Hz), 8.09 (1H, d, J = 13.9 Hz). 1-18

(E)-5-ethoxy-1,3- difluoro-2- (2-nitrovinyl) benzene ¹H-NMR (400 MHz,CDCl₃) δ 1.45 (3H, t, J = 7.1 Hz), 4.07 (2H, q, J = 7.1 Hz), 6.54 (2H,d, J = 10.4 Hz), 7.76 (1H, d, J = 13.8 Hz), 8.11 (1H, d, J = 13.8 Hz).1-19

(E)-3,5-difluoro- N,N-dimethyl-4- (2-nitrovinyl) aniline ¹H-NMR (400MHz, CDCl₃) δ 3.06 (6H, s), 6.22 (2H, d, J = 12.8 Hz), 7.71 (1H, d, J=13.4 Hz), 8.13 (1H, d, J = 13.4 Hz). 1-20

(E)-6-fluoro-5- (2-nitrovinyl) benzofuran ¹H-NMR (400 MHz, CDCl₃) δ6.81-6.82 (1H, m), 7.35 (1H, d, J = 11.0 Hz), 7.69- 7.79 (3H, m), 8.17(1H, d, J = 14.1 Hz). 1-21

(E)-2-methoxy- 5-(2-nitrovinyl) pyridine ¹H-NMR (400 MHz, CDCl₃) δ 4.00(3H, s), 6.83 (1H, d, J = 8.9 Hz), 7.53 (1H, d, J = 14.1 Hz), 7.76 (1H,dd, J = 8.9, 2.4 Hz), 7.98 (1H, d, J = 14.1 Hz), 8.35 (1H, d, J = 2.4Hz). 1-22

(E)-N-(3,5- difluoro-4-(2- nitrovinyl)phenyl) acetamide ¹H-NMR (400 MHz,CDCl₃) δ 2.22 (3H, s), 7.30 (2H, d, J = 10.4 Hz), 7.42 (1H, brs), 7.79(1H, d, J = 13.8 Hz), 8.10 (1H, d, J = 13.8 Hz), 1-23

(E)-[3,5-difluoro- 4-(2-nitrovinyl) phenyl](methyl) carbamic acidt-butyl ester ¹H-NMR (400MHz, CDCl₃) δ 1.53 (9H, s), 3.31 (3H, s), 7.09(2H, d, J = 11.0 Hz), 7.81 (1H, d, J = 14.1 Hz), 8.11 (1H, d, J = 14.1Hz).

TABLE 5 Ref. No Str. Chemical name P.D. 1-24

(E)-4,6-difluoro- 5-(2-nitrovinyl)- 2,3- dihydrobenzofuran ¹H-NMR (400MHz, CDCl₃) δ 3.29 (2H, t, J = 8.9 Hz), 4.76 (2H, t, J = 8.9 Hz), 6.48(1H, d, J = 10.4 Hz), 7.75 (1H, d, J = 14.1 Hz), 8.12 (1H, d, J = 14.1Hz). 1-25

(E)-tert-butyl {[6-fluoro-5-(2- nitrovinyl)-2,3- dihydro-1H-inden-1-yl]oxy} dimethylsilane ¹H-NMR (400 MHz, CDCl₃) δ 0.16 (3H, s),0.19 (3H, s), 0.95 (9H, s), 1.92-2.05 (1H, m), 2.45-2.52 (1H, m),2.72-2.80 (1H, m), 2.96 (1H, dd, J = 15.6, 6.4 Hz), 5.22 (1H, t, J = 7.6Hz), 7.07 (1H, d, J = 10.4 Hz), 7.32 (1H, d, J = 6.1 Hz), 7.70 (1H, d, J= 14.1 Hz), 8.05 (1H, d, J =14.1 Hz). 1-26

(E)-1-benzyl-6- fluoro-5-(2- nitrovinyl) indoline ¹H-NMR (400 MHz,CDCl₃) δ 3.04 (2H, t, J = 8.5 Hz), 3.61 (2H, t, J = 8.5 Hz), 4.38 (2H,s), 6.16 (1H, d, J = 12.1 Hz), 7.09 (1H, d, J = 6.7 Hz), 7.25-7.38 (5H,m), 7.55 (1H, d, J = 13.9 Hz), 8.05 (1H, d, J = 13.9 Hz). 1-27

(E)-3,5-difluoro- 4-(2-nitrovinyl) pyridine ¹H-NMR (400 MHz, CDCl₃) δ7.90 (1H, d, J = 14.1 Hz), 8.06 (1H, d, J = 14.1 Hz), 8.52 (2H, s).

Reference Example 2-1

(−)-(R*)-2-[1-(4-Methoxyphenyl)-2-nitroethyl]malonic acid dimethyl ester

Malonic acid dimethyl ester (0.36 mL) and nickel(II)bis[(S,S)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide (68 mg) wereadded to a solution of (E)-1-methoxy-4-(2-nitrovinyl)benzene (500 mg) intoluene (2.8 mL) under an argon atmosphere, and the mixture was stirredat room temperature for 6 hours. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (ethyl acetate:hexane=4:1), to obtain the title compoundas a colorless liquid (865 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.57 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 3.83(1H, d, J=9.1 Hz), 4.16-4.22 (1H, m), 4.83 (1H, dd, J=12.7, 9.1 Hz),4.89 (1H, dd, J=12.7, 5.1 Hz), 6.84 (2H, d, J=9.1 Hz), 7.14 (2H, d,J=9.1 Hz). [α]_(D) ²⁵=−20 (c 0.26, EtOH)

The following Reference Examples 2-2 to 2-28 were obtained using acorresponding nitrostyrene in the same method as in Reference Example2-1.

The structures and spectral data thereof are shown in Tables 6 to 12.

TABLE 6 Ref. No Str. Chemical name P.D. 2-2

(R*)-2-[1-(4- methoxy-2- methylphenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, DMSO- d₆) δ 2.40 (3H,s), 3.55 (3H, s),3.76 (3H, s), 3.77 (3H, s), 3.80 (1H, J = 9.1 Hz), 4.47-4.53 (1H, m),4.78-4.89 (2H, m), 6.69-6.72 (2H, m), 7.02-7.05 (1H, m). 2-3

(R*)-2-[1-(2- chloro-4- methoxyphenyl)- 2-nitroethyl] malonic aciddimethyl ester (¹H-NMR (400 MHz, CDCl₃) δ 3.64 (3H, s), 3.74 (3H, s),3.78 (3H, s), 4.08 (1H, d, J = 9.7 Hz), 4.64-4.70 (1H, m), 4.92 (1H, dd,J = 13.4, 4.3 Hz), 5.07 (1H, dd, J = 13.4, 8.6 Hz), 6.77 (1H, dd, J =8.6, 3.1 Hz), 6.94 (1H, d, J = 3.1 Hz), 7.14 (1H, d, J = 8.6 Hz). 2-4

(R*)-2-[1-(2- fluoro-4- methoxyphenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.57 (3H, s), 3.77 (6H, s),3.96 (1H, d, J = 9.7 Hz), 4.36 (1H, q, J = 9.7 Hz), 4.89 (2H, d, J = 6.7Hz), 6.59-6.64 (2H, m), 7.11 (1H, t, J = 8.8 Hz). 2-5

(R*)-2-[1-(3- fluoro-4- methoxyphenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.61 (3H, s), 3.77 (3H, s),3.80 (1H, d, J = 9.2 Hz), 3.86 (3H, s), 4.14-4.20 (1H, m), 4.79-4.91(2H, m), 6.87-6.99 (3H, m).

TABLE 7 Ref. No Str. Chemical name P.D. 2-6

(R*)-2-[1-(3,5- difluoro-4- methoxyphenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.65 (3H, s), 3.76-3.79 (1H,m), 3.77 (3H, s), 3.98 (3H, s), 4.14-4.19 (1H, m), 4.79-4.91 (2H, m),6.77-6.84 (2H, m). 2-7

(R*)-2-[1-(2,5- difluoro-4- methoxyphenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.61 (3H, s), 3.78 (3H, s),3.86 (3H, s), 3.92 (1H, d, J = 9.8 Hz), 4.30-4.37 (1H, m), 4.83-4.91(2H, m), 6.69 (1H, dd, J = 11.0, 7.3 Hz), 6.96 (1H, dd, J = 11.0, 7.3Hz). 2-8

(-)-(R*)-2-[1- (2,6-difluoro- 4-methoxyphenyl)- 2-nitroethyl] malonicacid dimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.57 (3H, s), 3.77 (3H,s), 3.80 (3H, s), 3.93 (1H, d, J = 10.4 Hz), 4.63-4.70 (1H, m), 4.81(1H, dd, J = 13.1, 10.1 Hz), 4.91 (1H, dd, J = 13.1, 4.7 Hz), 6.41-6.47(2H, m). [α]_(D) ²⁴ = −25 (c 0.11, EtOH) 2-9

(R*)-2-[1-(2,3- dihydrobenzofuran- 5-yl)-2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.17 (2H, t, J = 8.8 Hz), 3.59(3H, s), 3.76 (3H, s), 3.81 (1H, d, J = 9.2 Hz), 4.14-4.20 (1H, m), 4.55(2H, t, J = 8.8 Hz), 4.78-4.90 (2H, m), 6.70 (1H, d, J = 7.9 Hz), 6.94(1H, d, J = 7.9 Hz), 7.05 (1H, s). 2-10

(-)-(R*)-2-[1- (6-fluoro-2,3- dihydrobenzofuran- 5-yl)-2-nitroethyl]malonic acid dimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.13 (2H, t, J =8.9 Hz), 3.58 (3H, s), 3.77 (3H, s), 3.96 (1H, d, J = 9.8 Hz), 4.29-4.35(1H, m), 4.59 (2H, t, J = 8.9 Hz), 4.87 (2H, d, J = 7.3 Hz), 6.48 (1H,d, J = 11.6 Hz), 6.99 (1H, d, J = 7.3 Hz). [α]_(D) ²⁶ = −20 (c 0.31,EtOH)

TABLE 8 Ref. No Str. Chemical name P.D. 2-11

(R*)-2-[1-(7- fluorochroman-6- yl)-2-nitroethyl] malonic acid dimethylester ¹H-NMR (400 MHz, CDCl₃) δ 1.92-1.98 (2H, m), 2.68 (2H, t, J = 6.4Hz), 3.58 (3H, s), 3.77 (3H, s), 3.94 (1H, d, J = 9.8 Hz), 4.14 (2H, t,J = 4.9 Hz), 4.30 (1H, q, J = 7.3 Hz), 4.87 (2H, d, J = 7.3 Hz), 6.48(1H, d, J = 12.2 Hz), 6.84 (1H, d, J = 8.6 Hz). 2-12

(S*)-2-[1-(3- fluoro-5- methoxypridin-2- yl)-2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.66 (3H, s), 3.76 (3H, s),3.84 (3H, s), 3.98 (1H, d, J = 7 9 Hz), 4.62-4.67 (1H, m), 4.89 (1H, dd,J = 14.1, 4.3 Hz), 5.09 (1H, dd, J = 14.1, 9.5 Hz), 6.94 (1H, dd, J =11.0, 2.4 Hz), 8.05 (1H, d, J = 2.4 Hz). 2-13

(S*)-2-[1-(5- methoxythiophen- 2-yl)-2-nitroethyl] malonic acid dimethylester ¹H-NMR (400 MHz, CDCl₃) δ 3.70 (3H, s), 3.77 (3H, s), 3.84 (3H,s), 3.86 (1H, d, J = 7.9 Hz), 4.31-4.36 (1H, m), 4.81-4.89 (2H, m), 5.98(1H, d, J = 4.2 Hz), 6.55 (1H, d, J = 4.2 Hz). 2-14

(R*)-2-[1-(2,6- difluoro-4- hydroxyphenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.58 (3H, s), 3.80 (3H, s),3.92 (1H, d, J = 10.4 Hz), 4.62-4.69 (1H, m), 4.80 (1H, dd, J = 12.8,10.4 Hz), 4.91 (1H, dd, J = 12.8, 4.9 Hz), 5.79 (1H, brs), 6.35-6.41(2H, m). 2-15

(R*)-2-[1-(4-( methylthio) phenyl)-2- nitroethyl] malonic acid dimethylester ¹H-NMR (400 MHz, CDCl₃) δ 2.45 (3H, s), 3.59 (3H, s), 3.76 (3H,s), 3.83 (1H, d, J = 9.1 Hz), 4.17-4.23 (1H, m), 4.81-4.92 (2H, m), 7.14(2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz).

TABLE 9 Ref. No Str. Chemical name P.D. 2-16

2-[(1R*)-1-(4- methoxyphenyl)- 2-nitropropyl] malonic acid dimethylester ¹H-NMR (400 MHz, CDCl₃) δ 1.35 (0.6H, d, J = 6.7 Hz), 1.42 (2.4H,d, J = 6.7 Hz), 3.40-3.52 (6H, m), 3.72-4.41 (5H, m), 5.01-5.15 (1H, m),6.80-7.40 (4H, m). 2-17

(R*)-2-[1-(4- ethyl-2,6- difluorophenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.20 (3H, t, J = 7.6 Hz), 2.60(2H, q, J = 7.6 Hz), 3.55 (3H, s), 3.80 (3H, s), 3.95 (1H, d, J = 10.4Hz), 4.68-4.75 (1H, m), 4.84 (1H, dd, J = 13.4, 9.8 Hz), 4.93 (1H, dd, J= 13.4, 4.9 Hz), 6.73 (2H, dd, J = 14.1, 4.3 Hz).

TABLE 10 Ref. No Str. Chemical name P.D. 2-18

(R*)-2-{1-[4- (difluoromethoxy)- 2,6-difluorophenyl)-2-nitroethyl]malonic acid dimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.58(3H, s), 3.81 (3H, s), 3.93 (1H, d, J = 10.3 Hz), 4.71 (1H, dt, J =10.3, 4.2 Hz), 4.82 (1H, dd, J = 13.3, 10.3 Hz), 4.93 (1H, dd, J = 13.3,4.2 Hz), 6.50 (1H, t, J = 72.6 Hz), 6.69-6.74 (2H, m). 2-19

(R*)-2-[1-(4- ethoxy-2,6- difluorophenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.40 (3H, t, J = 7.1 Hz), 3.57(3H, s), 3.80 (3H, s), 3.92 (1H, d, J = 10.2 Hz), 3.96 (2H, q, J = 7.1Hz), 4.66 (1H, td, J = 10.2, 4.8 Hz),4.81 (1H, dd, J = 13.0, 10.2 Hz),4.91 (1H, dd, J = 13.0, 4.8 Hz), 6.39-6.45 (2H, m). 2-20

(R*)-2-{1-[4- (dimethylamino)- 2,6-difluorophenyl)- 2-nitroethyl]malonicacid dimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 2.92 (6H, s), 3.57 (3H,s), 3.79 (3H, s), 3.92 (1H, d, J = 10.4 Hz), 4.62 (1H, td, J = 10.4, 5.1Hz), 4.80 (1H, t, J = 11.3 Hz), 4.89 (1H, dd, J = 12.8, 4.9 Hz), 6.13(2H, d, J = 12.8 Hz). 2-21

(R*)-2-[1-(6- fluorobenzofuran- 5-yl)-2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.54 (3H, s), 3.78 (3H, s),4.06 (1H, d, J = 9.8 Hz), 4.49-4.55 (1H, m), 4.95 (1H, dd, J = 13.2, 5.2Hz), 4.99 (1H, dd, J = 13.2, 8.9 Hz), 6.71-6.72 (1H, m), 7.25 (1H, d, J= 12.8 Hz), 7.44 (1H, d, J = 7.3 Hz), 7.61 (1H, d, J = 2.4 Hz)

TABLE 11 Ref. No. Str. Chemical name P.D 2-22

(R*)-2-[1-(6- methoxypyridin- 3-yl)-2-nitro- ethyl]malonic acid dimethylester ¹H-NMR (400 MHz, CDCl₃) δ 3.62 (3H, s), 3.78 (3H, s), 3.83 (1H, d,J = 9.2 Hz), 3.91 (3H, s), 4.17-4.23 (1H, m), 4.80-4.93 (2H, m), 6.71(1H, d, J = 8.6 Hz), 7.47 (1H, dd, J = 8.6, 2.4 Hz), 8.05 (1H, d, J =2.4 Hz). 2-23

(R*)-2-[1-(4- acetamide-2,6- difluorophenyl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 2.18 (3H, s), 3.57 (3H, s),3.80 (3H, s), 3.94 (1H, d, J = 10.4 Hz), 4.66-4.73 (1H, m), 4.82 (1H,dd, J = 13.1, 10.1 Hz), 4.92 (1H, dd, J = 13.1, 4.9 Hz), 7.16 (2H, d, J= 10.2 Hz), 7.25 (1H, brs), 2-24

(R*)-2-(1-{4- [(tert-butoxy- carbonyl) (methyl)amino]- 2,6-difluoro-phenyl}-2- nitroethyl) malonic acid dimethyl ester ¹H-NMR (400 MHz,CDCl₃) δ 1.48 (9H, s), 3.23 (3H, s), 3.58 (3H, s), 3.80 (3H, s), 3.94(1H, d, J = 10.4 Hz), 4.67-4.75 (1H, m), 4.83 (1H, dd, J = 13.4, 9.8Hz), 4.93 (1H, dd, J = 13.4, 4.9 Hz), 6.92 (2H, d, J = 10.4 Hz). 2-25

(R*)-2-[1-(4,6- difluoro-2,3- dihydrobenzo- furan-5-yl)-2- nitroethyl]malonic acid dimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.20 (2H, t, J =8.6 Hz), 3.58 (3H, s), 3.80 (3H, s), 3.92 (1H, d, J = 11.0 Hz),4.62-4.69 (3H, m), 4.80 (1H, dd, J = 12.8, 9.8 Hz), 4.90 (1H, dd, J =12.8, 4.9 Hz), 6.34 (1H, d, J = 9.8 Hz).

TABLE 12 Ref. No. Str. Chemical name P.D 2-26

2-((1R*)-1-{1- [(tert-butyl- dimethylsilyl) oxy]-6-fluoro- 2,3-dihydro-1H-inden-5-yl}- 2-nitroethyl) malonic acid dimethyl ester ¹H-NMR (400MHz, CDCl₃) δ 0.14 (3H, s), 0.16 (3H, s), 0.94 (9H, d, J = 1.2 Hz),1.85-1.95 (1H, m), 2.39-2.46 (1H, m), 2.64-2.72 (1H, m), 2.84-2.90 (1H,m), 3.50 (1.5H, s), 3.60 (1.5H, s), 3.76 (1.5H, s), 3.77 (1.5H, s), 3.98(1H, dd, J = 9.8, 4.9 Hz), 4.36-4 .45 (1H, m), 4.87-4.97 (2H, m),5.15-5.19 (1H, m), 6.93-6.97 (1H, m), 7.01-7.04 (1H, m). 2-27

(R*)-2-[1-(1- benzyl-6-fluoro- indolin-5-yl)- 2-nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 2.89 (2H, t, J = 8.5 Hz), 3.37(2H, t, J = 8.5 Hz), 3.60 (3H, s), 3.76 (3H, s), 3.93 (1H, d, J = 9.7Hz), 4.20 (2H, s), 4.28 (1H, dt, J = 9.7, 7.3 Hz), 4.85 (2H, d, J = 7.3Hz), 6.11 (1H, d, J = 12.1 Hz), 6.82 (1H, d, J = 7.2 Hz), 7.28-7.36 (5H,m). 2-28

(R*)-2-[1-(3,5- difluoropyridin- 4-yl)-2- nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.60 (3H, s), 3.83 (3H, s),3.96 (1H, d, J = 9.8 Hz), 4.76 (1H, td, J = 9.9, 4.5 Hz), 4.88 (1H, dd,J = 13.8, 10.1 Hz), 4.97 (1H, dd, J = 13.8, 4.6 Hz), 8.36 (2H, s).

Reference Example 3-1

(+)-(S*)-2-[1-(4-Methoxyphenyl)-2-nitroethyl]malonic acid dimethyl ester

Nickel (II) bis[(R,R)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide wasused as a catalyst in place of nickel(II)bis[(S,S)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide, and the samemethod as in Reference Example 2-1 was performed to obtain the titlecompound.

¹H-NMR (400 MHz, CDCl₃) δ 3.57 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 3.83(1H, d, J=9.1 Hz), 4.16-4.22 (1H, m), 4.83 (1H, dd, J=12.7, 9.1 Hz),4.89 (1H, dd, J=12.7, 5.1 Hz), 6.84 (2H, d, J=9.1 Hz), 7.14 (2H, d,J=9.1 Hz).

[α]_(D) ²⁵=+14 (c 0.26, EtOH)

The same method as in Reference Example 3-1 was performed using acorresponding nitrostyrene to obtain the following Reference Examples3-2 to 3-8.

The structures and spectral data thereof are shown in Tables 13 to 14.

TABLE 13 Ref. No Str. Chemical name P.D. 3-2

(S*)-2-(2-nitro- 1-phenylethyl] malonic acid dimethyl ester ¹H-NMR (400MHz, CDCl₃) δ 3.57 (3H, s), 3.76 (3H, s), 3.87 (1H, d, J = 8.5 Hz),4.22-4.28 (1H, m), 4.85-4.95 (2H, m), 7.22-7.35 (5H, m). 3-3

(S*)-2-[1-(3- methoxyphenyl)- 2-nitroethyl] malonic acid dimethyl ester¹H-NMR (400 MHz, CDCl₃) δ 3.60 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 3.86(1H, d, J = 9.1 Hz), 4.18-4.25 (1H, m), 4.84-4.94 (2H, m), 6.75-6.83(3H, m), 7.23 (1H, t, J = 7.9 Hz). 3-4

(S*)-2-[1-(2- methoxyphenyl)- 2-nitroethyl] malonic acid dimethyl ester¹H-NMR (400 MHz, CDCl₃) δ 3.49 (3H, s), 3.73 (3H, s), 3.85 (3H, s), 4.16(1H, d, J = 9.6 Hz), 4.34-4.41 (1H, m), 4.86 (1H, dd, J = 13.0, 4.8 Hz),5.01 (1H, dd, J = 13.0, 9.6 Hz), 6.84-6.88 (2H, m), 7.12 (1H, dd, J =7.6, 1.8 Hz), 7.21-7.26 (1H, m). 3-5

(+)-(S*)-2-[1- (2,6-difluoro- 4-methoxy- phenyl)-2- nitroethyl] malonicacid dimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.57 (3H, s), 3.77 (3H,s), 3.80 (3H, s), 3.93 (1H, d, J = 10.4 Hz), 4.63-4.70 (1H, m), 4.81(1H, dd, J = 13.1, 10.1 Hz), 4.91 (1H, dd, J = 13.1, 4.7 Hz), 6.41-6.47(2H, m). [α] _(D) ²⁴ = +15 (c 0.07, EtOH) 3-6

(R*)-2-[1-(5- methoxythio- phen-2-yl)-2- nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.70 (3H, s), 3.77 (3H, s),3.84 (3H, s), 3.86 (1H, d, J = 7.9 Hz), 4.31-4.36 (1H, m), 4.81-4.89(2H, m), 5.98 (1H, d, J = 4.2 Hz), 6.55 (1H, d, J = 4.2 Hz).

TABLE 14 Ref. No Str. Chemical name P.D. 3-7

2-[(1S*)-1-(4- methoxyphenyl)- 2-nitropropyl] malonic acid dimethylester ¹H-NMR (400 MHz, CDCl₃) δ1.35 (0.6H, d, J = 6.7 Hz), 1.42 (2.4H,d, J = 6.7 Hz), 3.40-3.52 (6H, m), 3.72-4.41 (5H, m), 5.01-5.15 (1H, m),6.80-7.40 (4H, m). 3-8

(S*)-2-[1-(4- difluoromethoxy) phenyl)-2- nitroethyl] malonic aciddimethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.59 (3H, s), 3.77 (3H, s),3.83 (1H, d, J = 9.1 Hz), 4.22-4.28 (1H, m), 4.82-4.94 (2H, m), 6.49(1H, t, J = 73.6 Hz), 7.08 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5Hz).

Reference Example 4-1

(±)-2-[1-(4-Methoxyphenyl)-2-nitroethyl]malonic acid dimethyl ester

The same method as in Reference Example 2-1 was performed using(±)-Nickel(II) bis[N,N′-dibenzylcyclohexane-1,2-diamine]bromide as acatalyst in place of nickel(II)bis[(S,S)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide to obtain thetitle compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.57 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 3.83(1H, d, J=9.1 Hz), 4.16-4.22 (1H, m), 4.83 (1H, dd, J=12.7, 9.1 Hz),4.89 (1H, dd, J=12.7, 5.1 Hz), 6.84 (2H, d, J=9.1 Hz), 7.14 (2H, d,J=9.1 Hz).

Reference Example 5-1

2-(4-Methoxybenzylidene)malonic acid dimethyl ester

Piperidine (0.4 mL) and acetic acid (0.47 mL) were added to a solutionof p-anisaldehyde (5.0 mL) and malonic acid dimethyl ester (4.7 mL) inbenzene (0.9 mL) under an argon atmosphere, to produce a reactionsolution. The reaction solution was heated to reflux with a Dean-Starkapparatus for 3 hours. Ethyl acetate was added to the reaction solution,and the mixture was washed with a 1 mol/L hydrochloric acid, a saturatedaqueous sodium hydrogen carbonate solution, and a brine successively,and dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was then purified by silica gel columnchromatography (ethyl acetate:hexane=4:1), to obtain the title compoundas a white solid (9.5 g).

¹H-NMR (400 MHz, CDCl₃) δ 3.83 (3H, s), 3.84 (3H, s), 3.87 (3H, s), 6.90(2H, d, J=8.6 Hz), 7.39 (2H, d, J=8.6 Hz), 7.71 (s, 1H).

Reference Example 6-1

(±)-2-[1-(4-Methoxyphenyl)-2-methyl-2-nitropropyl]malonic acid dimethylester

2-Nitropropane (0.14 mL) and potassium fluoride supported on alumina(KF/Al₂O₃) (400 mg) were added to a solution of2-(4-methoxybenzylidene)malonic acid dimethyl ester (250 mg) in dimethylsulfoxide (0.8 mL) under an argon atmosphere, to produce a reactionsolution. The reaction solution was stirred at room temperature for 1hour and a half. Diethyl ether was added to the reaction solution, theinsoluble was removed by filtration, and the solution was washed withwater and a brine successively, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue was thenpurified by silica gel column chromatography (ethyl acetate:hexane=4:1),to obtain the title compound as a white solid (298 mg).

¹H-NMR (400 MHz, CDCl₃) δ 1.43 (3H, s), 1.64 (3H, s), 3.35 (3H, s), 3.75(3H, s), 3.78 (3H, s), 4.22 (2H, s), 6.81 (2H, d, J=9.1 Hz), 7.10 (2H,d, J=9.1 Hz).

Reference Example 6-2

(±)-2-[(4-Methoxyphenyl)-(1-nitrocyclopentyl)methyl]malonic aciddimethyl ester

The same method as in Reference Example 6-1 was performed usingnitrocyclopentane in place of 2-nitropropane to obtain the titlecompound.

1H-NMR (400 MHz, CDCl3) δ1.43-1.86 (6H, m), 2.33-2.42 (1H, m), 2.45-2.53(1H, m), 3.35 (3H, s), 3.77 (3H, s), 3.80 (3H, s), 4.14 (1H, d, J=11.5Hz), 4.31 (1H, d, J=11.5 Hz), 6.80 (2H, d, J=8.5 Hz), 7.04 (2H, d, J=9.1Hz).

Reference Example 6-3

(±)-2-[(4-Methoxyphenyl)-(1-nitrocyclohexyl)methyl]malonic acid dimethylester

The same method as in Reference Example 6-1 was performed usingnitrocyclohexane in place of 2-nitropropane to obtain the titlecompound.

¹H-NMR (400 MHz, CDCl₃) δ1.10-1.17 (2H, m), 1.22-1.68 (6H, m), 2.35-2.44(2H, m), 3.28 (3H, s), 3.78 (3H, s), 3.79 (3H, s), 3.94 (1H, d, J=10.9Hz), 4.32 (1H, d, J=10.9 Hz), 6.79 (2H, d, J=7.9 Hz), 7.02 (2H, brd,J=7.9 Hz).

Reference Example 7-1

(−)-(3S*,4R*)-4-(4-Methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester

Nickel(II) chloride hexahydrate (1.3 g) was added to a solution of(R*)-2-[1-(4-methoxyphenyl)-2-nitroethyl]malonic acid dimethyl ester(1.7 g) in methanol (110 mL) under an argon atmosphere, to produce areaction solution. To the reaction solution, sodium borohydride (1.03 g)was added in several doses under ice-cooling, and the reaction solutionwas warmed to room temperature, and stirred for 2 hours. A saturatedaqueous ammonium chloride solution and ethyl acetate were added to thereaction solution, and the mixture was stirred at room temperature for 1hour. The mixture was extracted with ethyl acetate, and the extract waswashed with water and a brine successively, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and thecrude product was washed with ethanol-diisopropyl ether, to obtain thetitle compound as a white solid (840 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.40 (1H, t, J=9.1 Hz), 3.53 (1H, d, J=9.7Hz), 3.76-3.81 (1H, m), 3.78 (3H, s), 3.80 (3H, s), 4.08 (1H, q, J=8.9Hz), 5.85 (1H, brs), 6.88 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz).

[α]_(D) ²⁵=−96 (c 0.19, EtOH)

The same method as in Reference Example 7-1 was performed using acorresponding nitro substance to obtain the following Reference Examples7-2 to 7-42. The structures and spectral data thereof are shown inTables 15 to 25.

TABLE 15 Ref. No Str. Chemical name P.D. 7-2

(3S*,4R*)-4-(3- fluoro-4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylicacid methyl ester 1H-NMR (400 MHz, CDCl₃) δ 3.38 (1H, t, J = 8.9 Hz),3.50 (1H, d, J = 9.8 Hz), 3.76-3.81 (1H, m), 3.79 (3H, s), 3.88 (3H, s),4.06 (1H, q, J = 8.8 Hz), 5.94 (1H, brs), 6.90-7.01 (3H. m).

TABLE 16 Ref. No Str. Chemical name P.D. 7-3

(3S*,4R*)-4-(2- fluoro-4-methoxy- phenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.44 (1H, dd, J =9.7, 7.9 Hz), 3.68 (1H, d, J = 9.7 Hz), 3.75-3.79 (1H, m), 3.78 (3H, s),3.79 (3H, s) 4.22 (1H, q, J = 8.9 Hz), 6.15 (1H, s), 6.62-6.68 (2H, m),7.15 (1H, t, J = 8.5 Hz). 7-4

(3S*,4R*)-4-(2- chloro-4-methoxy- phenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.35-3.41 (1H,m), 3.67 (1H, d, J = 8.6 Hz), 3.79 (3H, s), 3.80 (3H, s), 3.89 (1H, t, J= 8.6 Hz), 4.47 (1H, q, J = 7.9 Hz), 5.70 (1H, brs), 6.82 (1H, dd, J =8.6, 2.4 Hz), 6.95 (1H, d, J = 2.4 Hz), 7.20 (2H, t, J = 8.6 Hz). 7-5

(3S*,4R*)-4-(4- methoxy-2-methyl- phenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, DMSO-d₆) δ 2.36 (3H, s),3.29-3.36 (1H, m), 3.57 (1H, d, J = 9.1 Hz), 3.76-3.81 (1H, m), 3.77(3H, s), 3.78 (3H, s), 4.31 (1H, q, J = 8.4 Hz), 6.09 (1H, brs), 6.73(1H, d, J = 3.0 Hz), 6.76 (1H, dd, J = 8.5, 3.0 Hz), 7.17 (1H, d, J =8.5 Hz). 7-6

(3S*,4R*)-4-(3,5- difluoro-4- methoxyphenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.37 (1H, t, J =8.6 Hz), 3.47 (1H, d, J = 9.8 Hz), 3.77-3.81 (1H, m), 3.81 (3H, s), 3.98(3H, s) 4.05 (1H, q, J = 8.8 Hz), 5.69 (1H, brs), 6.78-6.85 (2H, m). 7-7

(3S*,4R*)-4-(2,5- difluoro-4- methoxyphenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.42 (1H, t, J =8.9 Hz), 3.62 (1H, d, J = 9.8 Hz), 3.75-3.81 (1H, m), 3.79 (3H, s), 3.87(3H, s) 4.20 (1H, q, J = 8.9 Hz), 6.14 (1H, brs) 6.71 (1H, dd, J = 11.0,7.3 Hz), 6.98 (1H, dd, J = 11.0, 7.3 Hz).

TABLE 17 Ref. No Str. Chemical name P.D. 7-8

(−)-(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.51 (1H, t, J= 9.2 Hz), 3.64-3.70 (1H, m), 3.78 (6H, s), 3.78-3.81 (1H, m), 4.46 (1H,q, J = 9.4 Hz), 6.24 (1H, brs), 6.43-6.50 (2H, m). [α]_(D) ²³ = −120 (c0.11, EtOH) 7-9

(3S*,4R*)-4- (2,3-dihydro- benzofuran-5- yl)-2-oxo- pyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.20 (2H, t, J =8.8 Hz), 3.38 (1H, t, J = 8.9 Hz), 3.53 (1H, d, J = 9.8 Hz), 3.77 (1H,t, J = 9.0 Hz), 3.78 (3H, s) 4.06 (1H, q, J = 9.0 Hz), 4.57 (2H, t, J =8.8 Hz), 5.94 (1H, brs), 6.74 (1H, d, J = 7.9 Hz), 6.99 (1H, d, J = 7.9Hz), 7.09 (1H, s). 7-10

(−)-(3S*,4R*)- 4-(6-fluoro-2,3- dihydrobenzo- furan-5-yl)-2-oxopyrrolidine- 3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ3.15 (2H, t, J = 8.9 Hz), 3.41 (1H, t, J = 8.6 Hz), 3.66 (1H, d, J = 9.8Hz), 3.74-3.79 (1H, m), 3.79 (3H, s), 4.19 (1H, q, J = 8.6 Hz), 4.61(2H, t, J = 8.9 Hz), 5.68 (1H, brs), 6.52 (1H, d, J = 11.6 Hz), 7.03(1H, d, J = 7.9 Hz). [α] _(D) ²⁶ = −121 (c 0.20, EtOH) 7-11

(3S*,4R*)-4-(7- fluorochroman- 6-yl)-2-oxo- pyrrolidine-3- carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.94-2.01 (2H, m), 2.71 (2H,t, J = 6.1 Hz), 3.42 (1H, t, J = 8.9 Hz), 3.67 (1H, d, J = 9.8 Hz),3.73-3.78 (1H, m), 3.78 (3H, s), 4.11-4.17 (3H, m), 5.68 (1H, brs), 6.52(1H, d, J = 11.6 Hz), 6.87 (1H, d, J = 7.9 Hz).

TABLE 18 Ref. No Str. Chemical name P.D. 7-12

(3S*,4R*)-4-(3- fluoro-5- methoxypyridin- 2-yl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.53 (1H, t, J= 8.6 Hz), 3.77-3.81 (1H, m), 3.79 (3H, s), 3.86 (3H, s), 4.04 (1H, d, J= 9.2 Hz), 4.52 (1H, q, J = 8.8 Hz), 5.72 (1H, brs), 6.94 (1H, dd, J =11.0, 2.4 Hz), 8.11 (1H, d, J = 2.4 Hz). 7-13

(3S*,4R*)-4-(5- methoxythiophen- 2-yl)-2- oxopyrrolidine-3- carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.41 (1H, t, J = 9.1 Hz),3.49 (1H, d, J = 10.3 Hz), 3.75-3.79 (1H, m), 3.81 (3H, s), 3.86 (3H,s), 4.22 (1H, q, J = 9.1 Hz), 5.78 (1H, brs), 6.01 (1H, d, J = 4.2 Hz),6.54 (1H, d, J = 4.2 Hz). 7-14

(3S*,4R*)-4-(2,6- difluoro-4- hydroxyphenyl)- 2-oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.25 (1H, t, J= 9.2 Hz), 3.52-3.59 (2H, m), 3.63 (3H, s), 4.12 (1H, q, J = 9.6 Hz),6.43-6.49 (2H, m), 8.27 (1H, s), 10.41 (1H, brs). 7-15

(3S*,4R*)-4-(4- methoxythio- phenyl)-2- oxopyrrolidine-3- carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 2.48 (3H, s), 3.41 (1H, t, J= 8.9 Hz), 3.54 (1H, d, J = 9.7 Hz), 3.78 (3H, s), 3.80 (1H, t, J = 8.9Hz), 4.10 (1H, q, J = 8.9 Hz), 5.92 (1H, brs), 7.18 (2H, d, J = 8.5 Hz),7.24 (2H, d, J = 8.5 Hz). 7-16

(3S*,4R*,5S*)-4- (4-methoxy- phenyl)-5-methyl- 2-oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, DMSO-d₆) δ 0.67 (3H, d,J = 6.7 Hz), 3.60 (3H, s), 3.72 (3H, s), 3.80-3.90 (1H, m), 3.95-4.05(2H, m), 6.88 (2H, d, J = 9.1 Hz), 7.21 (2H, d, J = 9.1 Hz), 8.21 (1H,s).

TABLE 19 Ref. No Str. Chemical name P.D. 7-17

(3S*,4R*,5R*)- 4-(4-methoxy- phenyl)-5- methyl-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.27 (3H, d, J= 6.1 Hz), 3.49 (1H, dd, J = 10.9, 8.5 Hz), 3.63 (1H, d, J = 10.9 Hz),3.68-3.73 (1H, m), 3.74 (3H, s), 3.80 (3H, s), 5.65 (1H, s), 6.89 (2H,d, J = 9.1 Hz), 7.19 (2H, d, J = 9.1 Hz). 7-18

(3S*,4R*)-4-(4- ethyl-2,6- difluorophenyl)- 2-oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.22 (3H, t, J= 7.6 Hz), 2.62 (2H, q, J = 7.6 Hz), 3.53 (1H, t, J = 9.2 Hz), 3.68 (1H,t, J = 9.2 Hz), 3.78 (3H, s), 3.83 (1H, d, J = 9.8 Hz), 4.52 (1H, q, J =9.8 Hz), 6.03 (1H, brs), 6.75 (2H, dd, J = 12.2, 3.1 Hz). 7-19

(3R*,4S*)-2-oxo- 4-phenyl- pyrrolidine-3- carboxylic acid methyl ester¹H-NMR (400 MHz, CDCl₃) δ 3.44 (1H, dd, J = 9.7, 8.5 Hz), 3.59 (1H, d, J= 9.7 Hz), 3.79 (3H, s), 3.80-3.85 (1H, m), 4.14 (1H, q, J = 8.9 Hz),5.82 (1H, brs), 7.25-7.38 (5H, m). 7-20

(+)-(3R*,4S*)-4- (4-methoxy- phenyl)-2- oxopyrrolidine-3- carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.40 (1H, t, J = 9.1 Hz),3.53 (1H, d, J = 9.7 Hz), 3.76-3.81 (1H, m), 3.78 (3H, s), 3.80 (3H, s),4.08 (1H, q, J = 8.9 Hz), 5.85 (1H, brs), 6.88 (2H, d, J = 8.5 Hz), 7.18(2H, d, J = 8.5 Hz). [α] _(D) ²⁵ = +89 (c 0.16, EtOH)

TABLE 20 Ref. No Str. Chemical name P.D. 7-21

(3R*,4S*)-4-(3- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylic acidmethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.43 (1H, t, J = 8.6 Hz), 3.59(1H, d, J = 9.7 Hz), 3.79 (3H, s), 3.79-3.84 (1H, m), 3.81 (3H, s),4.05-4.15 (1H, m), 6.05-6.25 (1H, br), 6.76-6.86 (3H, m), 7.27 (1H, t, J= 8.0 Hz). 7-22

(3R*,4S*)-4-(2- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylic acidmethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.49 (1H, t, J = 8.5 Hz), 3.73(1H, d, J = 9.2 Hz), 3.77 (3H, s), 3.83 (3H, s), 3.84 (1H, d, J = 9.2Hz), 4.26 (1H, q, J = 8.5, Hz), 5.85 (1H, brs), 6.89-6.95 (2H, m), 7.20(1H, dd, J = 7.3, 1.8 Hz), 7.27-7.30 (1H, m). 7-23

(+)-(3R*,4S*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.51 (1H, t, J= 9.2 Hz), 3.64-3.70 (1H, m), 3.78 (6H, s), 3.78-3.81 (1H, m), 4.46 (1H,q, J = 9.4 Hz), 6.24 (1H, brs), 6.43-6.50 (2H, m). [α] _(D) ²⁴ = +105 (c0.09, EtOH) 7-24

(3R*,4S*,5R*)- 4-(4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylic acidmethyl ester ¹H-NMR (400 MHz, DMSO-d₆) δ 0.67 (3H, d, J = 6.7 Hz), 3.60(3H, s), 3.72 (3H, s), 3.80-3.90 (1H, m), 3.95-4.05 (2H, m), 6.88 (2H,d, J = 9.1 Hz), 7.21 (2H, d, J = 9.1 Hz), 8.21 (1H, s). 7-25

(3R*,4S*,5S*)- 4-(4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylic acidmethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.27 (3H, d, J = 6.1 Hz), 3.49(1H, dd, J = 10.9, 8.5 Hz), 3.63 (1H, d, J = 10.9 Hz), 3.68-3.73 (1H,m), 3.74 (3H, s), 3.80 (3H, s), 5.65 (1H, s), 6.89 (2H, d, J = 9.1 Hz),7.19 (2H, d, J = 9.1 Hz).

TABLE 21 Ref. No Str. Chemical name P.D. 7-26

(3R*,4R*)-4-(5- methoxythiophen- 2-yl)-2- oxopyrrolidine-3- carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.41 (1H, t, J = 9.1 Hz),3.49 (1H, d, J = 10.3 Hz), 3.75-3.79 (1H, m), 3.81 (3H, s), 3.86 (3H,s), 4.22 (1H, q, J = 9.1 Hz), 5.78 (1H, s), 6.01 (1H, d, J = 4.2 Hz),6.54 (1H, d, J = 4.2 Hz). 7-27

(3R*,4S*)-4-[4- (difluoromethoxy) phenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.39-3.44 (1H,m), 3.54 (1H, d, J = 9.7 Hz), 3.80 (3H, s), 3.80 (1H, t, J = 9.2 Hz),4.12 (1H, q, J = 8.8 Hz), 5.98 (1H, brs), 6.50 (1H, t, J = 73.6 Hz),7.12 (2H, d, J = 9.2 Hz), 7.22-7.26 (2H, m). 7-28

(±)-trans-4-[4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylic acidmethyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.40 (1H, t, J = 9.1 Hz), 3.53(1H, d, J = 9.7 Hz), 3.76-3.81 (1H, m), 3.78 (3H, s), 3.80 (3H, s), 4.08(1H, q, J = 8.9 Hz), 5.85 (1H, brs), 6.88 (2H, d, J = 8.5 Hz), 7.18 (2H,d, J = 8.5 Hz). 7-29

(±)-trans-4-(4- methoxyphenyl)- 5,5-dimethyl-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ0.92 (3H, s), 1.39(3H, s), 3.72 (3H, s), 3.80 (1H, d, J = 12.1 Hz), 3.81 (3H, s), 3.93(1H, d, J = 12.1 Hz), 5.90 (1H, s), 6.89 (2H, d, J = 8.6 Hz), 7.18 (2H,d, J = 8.6 Hz).

TABLE 22 Ref. No Str. Chemical name P.D. 7-30

(±)-trans-4-(4- methoxyphenyl)- 2-oxo-1- azaspiro[4,4] nonane-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ1.21-1.67 (6H, m),1.77-1.85 (1H, m), 1.88-1.95 (1H, m), 3.72 (3H, s), 3.80 (3H, s), 3.85(1H, d, J = 11.0 Hz), 3.97 (1H, d, J = 11.0 Hz), 6.01 (1H, brs), 6.88(2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz). 7-31

(±)-trans-4-(4- methoxyphenyl)- 2-oxo-1- azaspiro[4,5] decane-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ0.78-0.89 (1H, m),0.92-1.07 (1H, m), 1.16-1.34 (2H, m), 1.41-1.51 (2H, m), 1.52-1.80 (4H,m), 3.69 (1H, d, J = 12.1 Hz), 3.72 (3H, s), 3.81 (3H, s), 3.93 (1H, d,J = 12.1 Hz), 6.22 (1H, brs), 6.88 (2H, d, J = 9.1 Hz), 7.15 (2H, d, J =9.1 Hz).

TABLE 23 Ref. No. Str. Chemical name P.D. 7-32

(3S*,4R*)-4-[4- (difluoromethoxy)- 2,6-difluoro- phenyl]-2-oxopyrrolidine-3- carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ3.52 (1H, t, J = 9.1 Hz), 3.68-3.73 (1H, m), 3.79-3.82 (4H, m),4.49-4.56 (1H, m), 6.27 (1H, br), 6.51 (1H, t, J = 72.1 Hz), 6.72-6.78(2H, m). 7-33

(3S*,4R*)-4-(4- ethoxy-2,6- difluorophenyl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.40 (3H, t, J =7.1 Hz), 3.51 (1H, t, J = 8.9 Hz), 3. 67 (1H, t, J = 9.5 Hz), 3.78 (3H,s), 3.79 (1H, d, J = 11.0 Hz), 3.98 (2H, q, J = 7.1 Hz), 4.42-4.49 (1H,m), 6.33 (1H, s), 6.42-6.48 (2H, m). 7-34

(3S*,4R*)-4-[4- (dimethylamino)- 2,6-difluoro- phenyl]-2-oxopyrrolidine-3- carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ2.93 (6H, s), 3.50 (1H, t, J = 9.2 Hz), 3.64 (1H, t, J = 9.5 Hz),3.77-3.80 (4H, m), 4.42 (1H, q, J = 9.6 Hz), 5.83 (1H, s), 6.18 (2H, d,J = 12.2 Hz). 7-35

(3S*,4R*)-4-(6- fluorobenzofuran- 5-yl)-2- oxopyrrolidine-3- carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.50 (1H, t, J = 8.9 Hz),3.78 (1H, d, J = 10.4 Hz), 3.79 (3H, s), 3.86 (1H, t, J = 8.9 Hz),4.34-4.40 (1H, m), 6.04 (1H, s), 6.74 (1H, d, J = 1.5 Hz), 7.25-7.28(1H, m), 7.47 (1H, d, J = 7.3 Hz), 7.63 (1H, d, J = 1.5 Hz).

TABLE 24 Ref. No. Str. Chemical name P.D. 7-36

(3S*,4R*)-4-(6- methoxypyridin- 3-yl)-2- oxopyrrolidine- 3-carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.39 (1H, t, J = 9.2 Hz),3.51 (1H, d, J = 9.8 Hz), 3.80 (3H, s), 3.78-3.83 (1H, m), 3.93 (3H, s),4.05-4.11 (1H, m), 6.23 (1H, brs), 6.76 (1H, d, J = 8.6 Hz), 7.49 (1H,dd, J = 8.6, 2.4 Hz), 8.08 (1H, d, J = 2.4 Hz). 7-37

(3S*,4R*)-4-(4- acetamide-2,6- difluorophenyl)- 2-oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 2.19 (3H, s),3.52 (1H, t, J = 9.2 Hz), 3.66-3.72 (1H, m), 3.78 (3H, s), 3.78-3.81(1H, m), 4.50 (1H, q, J = 9.4 Hz), 5.88 (1H, s), 7.17 (2H, d, J = 10.4Hz), 7.32 (1H, s). 7-38

(3S*,4R*)-4-{4- [(tert-butoxy carbonyl)(methyl) amino]-2,6-difluorophenyl}- 2-oxopyrrolidine- 3-carboxylic acid methyl ester ¹H-NMR(400 MHz, CDCl₃) δ 1.49 (9H, s), 3.25 (3H, s), 3.53 (1H, t, J = 8.9 Hz),3.66-3.72 (1H, m), 3.79 (3H, s), 3.82 (1H, d, J = 9.8 Hz), 4.52 (1H, q,J = 9.4 Hz), 5.99 (1H, brs), 6.92 (2H, d, J = 10.4 Hz). 7-39

(3S*,4R*)-4-(4,6- difluoro-2,3- dihydrobenzo- furan-5-yl)-2-oxopyrrolidine-3- carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ3.21 (2H, t, J = 8.6 Hz), 3.50 (1H, dd, J = 11.6, 6.7 Hz), 3.66 (1H, t,J = 8.9 Hz), 3.77-3.80 (4H, m), 4.46 (1H, q, J = 9.4 Hz), 4.65 (2H, t, J= 8.6 Hz), 6.16 (1H, s), 6.37 (1H, d, J = 10.4 Hz).

TABLE 25 Ref. No. Str. Chemical name P.D. 7-40

(3S*,4R*)-4-{1- [(tert-butyl- dimethylsilyl) oxy]-6-fluoro-2,3-dihydro-1H- inden-5-yl}-2- oxopyrrolidine- 3-carboxylic acid methylester ¹H-NMR (400 MHz, CDCl₃) δ 0.14 (3H, s), 0.17 (3H, s), 0.94 (9H,s), 1.87-1.97 (1H, m), 2.41-2.49 (1H, m), 2.67-2.75 (1H, m), 2.91 (1H,dd, J = 15.9, 6.7 Hz), 3.41-3.46 (1H, m), 3.68-3.72 (1H, m), 3.75-3.81(4H, m), 4.22-4.29 (1H, m), 5.20 (1H, t, J = 7.0 Hz), 5.82 (1H, s), 6.98(1H, d, J = 10.4 Hz), 7.07 (1H, d, J = 6.7 Hz). 7-41

(3S*,4R*)-4-(1- benzyl-6- fluoroindolin-5- yl)-2- oxopyrrolidine-3-carboxylic acid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 2.93 (2H, t, J =8.6 Hz), 3.37-3.43 (3H, m), 3.65 (1H, d, J = 9.8 Hz), 3.70-3.75 (1H, m),3.78 (3H, s), 4.11-4.19 (1H, m), 4.22 (2H, s), 5.81 (1H, br), 6.16 (1H,d, J = 11.6 Hz), 6.89 (1H, d, J = 7.9 Hz), 7.28-7.36 (5H, m). 7-42

(3S*,4R*)-4-(3,5- difluoropyridin- 4-yl)-2- oxopyrrolidine-3- carboxylicacid methyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.56 (1H, t, J = 9.2 Hz),3.76-3.85 (5H, m), 4.60 (1H, q, J = 9.2 Hz), 5.91 (1H, s), 8.37 (2H, s).

Reference Example 7-43

(3S*,4R*)-4-(6-Fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid methyl ester

A 1 mol/L hydrochloric acid (15 mL) was added to a solution of(3S*,4R*)-4-{1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-5-yl}-2-oxopyrrolidine-3-carboxylicacid methyl ester (2.0 g) in tetrahydrofuran (25 mL) under an argonatmosphere to produce a reaction solution. The reaction solution wasstirred at room temperature for 8 hours. The reaction solution wasextracted with ethyl acetate, and the extract was washed with water anda brine successively, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was thenpurified by silica gel column chromatography (hexane:ethyl acetate=4:1followed by 1:4), to obtain the title compound as a colorless amorphous(1.37 g).

¹H-NMR (400 MHz, CDCl₃) δ 1.80 (1H, dd, J=7.3. 4.3 Hz), 1.92-2.01 (1H,m), 2.49-2.57 (1H, m), 2.73-2.81 (1H, m), 2.96-3.03 (1H, m), 3.44 (1H,t, J=8.9 Hz), 3.70 (1H, dd, J=9.5, 2.1 Hz), 3.78-3.83 (4H, m), 4.27 (1H,q, J=8.8 Hz), 5.21 (1H, q, J=6.3 Hz), 5.87 (1H, s), 7.11 (1H, d, J=4.3Hz), 7.13 (1H, s).

Reference Example 7-44

(3S*,4R*)-4-(6-Fluoro-2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylicacid methyl ester

10% Palladium on carbon (100 mg) was added to a solution of(3S*,4R*)-4-(6-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid methyl ester (200 mg) in methanol (5 mL)under an argon atmosphere to produce a reaction solution. The reactionsolution was stirred at room temperature under a hydrogen atmosphere for4 hours. The reaction solution was filtered over Celite and washed withethyl acetate. The solvent was removed under reduced pressure to obtainthe title compound as a colorless amorphous (170 mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.05-2.13 (2H, m), 2.83-2.89 (4H, m), 3.44(1H, t, J=8.9 Hz), 3.70 (1H, d, J=9.8 Hz), 3.76-3.81 (4H, m), 4.25 (1H,q, J=8.8 Hz), 5.67 (1H, s), 6.92 (1H, d, J=10.4 Hz), 7.08 (1H, d, J=6.7Hz).

Reference Example 8-1

(−)-(3S*,4R*)-4-(4-Methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid

A 2 mol/L sodium hydroxide aqueous solution (0.52 mL) was added to asolution of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester (130 mg) in methanol (2.6 mL) to produce a reactionsolution. The reaction solution was stirred at 60° C. for 1 hour. A 1mol/L hydrochloric acid was added to the reaction solution to make thereaction solution acidic (pH: 1), and the mixture was extracted withethyl acetate. The organic layer was washed with water and a s brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the crude product was washed withethyl acetate-diisopropyl ether, to obtain the title compound as a whitesolid (112 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.16 (1H, t, J=9.4 Hz), 3.42 (1H, d, J=10.9Hz), 3.55 (1H, t, J=8.2 Hz), 3.72 (3H, s), 3.79 (1H, q, J=9.5 Hz), 6.88(2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 8.03 (1H, s), 12.54 (1H,brs).

[α]_(D) ²⁷=−68 (c 0.15, EtOH)

The same method as in Reference Example 8-1 was performed using acorresponding ester substance to obtain the following Reference Examples8-2 to 8-41. The structures and spectral data thereof are shown inTables 26 to 35.

TABLE 26 Ref. No Str. Chemical name P.D. 8-2

(3S*,4R*)-4-(3- fluoro-4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.16 (1H, t, J = 9.4 Hz), 3.47 (1H, d,J = 10.9 Hz), 3.54 (1H, t, J = 8.2 Hz), 3.75-3.84 (1H, m), 3.80 (3H, s),7.06-7.12 (2H. m), 7.24-7.28 (1H, m), 8.05 (1H, s), 12.65 (1H, brs). 8-3

(3S*,4R*)-4-(2- fluoro-4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.18 (1H, t, J = 9.1 Hz), 3.48 (1H, d,J = 10.3 Hz), 3.55 (1H, t, J = 9.1 Hz), 3.74 (3H, s), 4.00 (1H, q, J =10.3), 6.75-6.83 (2H, m), 7.37 (1H. t, J = 8.8 Hz), 8.09 (1H, s), 12.66(1H, brs). 8-4

(3S*,4R*)-4-(2- chloro-4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.11 (1H, t, J = 9.2 Hz), 3.54-3.61(2H, m), 3.75 (3H, s), 4.20 (1H, q, J = 9.0 Hz), 6.93 (1H, dd, J = 8.9,2.8 Hz), 7.02 (1H, d, J = 2.8 Hz), 7.49 (1H, d, J = 8.9 Hz), 8.10 (1H,s), 12.67 (1H, brs). 8-5

(3S*,4R*)-4-(4- methoxy-2- methylphenyl)- 2-oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, DMSO-d₆) δ 2.28 (3H, s), 3.08 (1H, t, J = 9.1 Hz),3.44 (1H, d, J = 10.3 Hz), 3.55 (1H, t, J = 9.1 Hz), 3.70 (3H, s),3.97-4.04 (1H, m), 6.72-6.76 (2H, m), 7.33 (1H, d, J = 7.9 Hz), 8.04(1H, s), 12.61 (1H, brs). 8-6

(3S*,4R*)-4-(3, 5-difluoro-4- methoxyphenyl)- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.15 (1H, t, J = 9.5 Hz),3.52-3.57 (2H, m), 3.83 (1H, q, J = 9.6 Hz), 3.88 (3H, s), 7.15-7.22(2H, m), 8.08 (1H, s), 12.68 (1H, brs).

TABLE 27 Ref. No Str. Chemical name P.D. 8-7

(3S*,4R*)-4-(2, 5-difluoro-4- methoxyphenyl)- 2- oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.18 (1H, t, J = 9.5 Hz),3.49-3.55 (2H, m), 3.82 (3H, s), 4.02 (1H, q, J = 9.5 Hz), 7.10 (1H, dd,J = 12.2, 7.3 Hz), 7.44 (1H, dd, J = 12.2, 7.3 Hz), 8.11 (1H, s), 12.67(1H, brs). 8-8

(−)-(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.25 (1H, t, J = 9.2 Hz),3.43 (1H, d, J = 10.4 Hz), 3.56 (1H, t, J = 9.2 Hz), 3.76 (3H, s), 4.14(1H, q, J = 9.4 Hz), 6.73-6.80 (2H, m), 8.20 (1H, s), 12.77 (1H, brs).[α]_(D) ²³ = −121 (c 0.10, EtOH) 8-9

(3S*,4R*)-4-(6- fluoro-2,3- dihydrobenzofuran- 5-yl)-2-oxopyrrolidine-3- carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.10-3.17(3H, m), 3.41 (1H, d. J = 11.0 Hz), 3.53 (1H, t, J = 8.9 Hz), 3.77 (1H,q, J = 9.6 Hz), 4.48 (2H, t, J = 8.6 Hz), 6.68 (1H, d, J = 8.6 Hz), 7.02(1H, d, J = 8.6 Hz), 7.20 (1H, s), 8.03 (1H, s), 12.62 (1H, brs). 8-10

(−)-(3S*,4R*)- 4-(6-fluoro-2,3- dihydrobenzofuran- 5-yl)-2-oxopyrrolidine- 3-carboxylic acid 1H-NMR (400 MHz, DMSO-d₆) δ 3.09-3.19(3H, m), 3.46 (1H, d. J = 10.4 Hz), 3.52 (1H, t, J = 8.9 Hz), 3.94-4.03(1H, m), 4.55 (2H, t, J = 8.6 Hz), 6.65 (1H, d, J = 11.0 Hz), 7.31 (1H,d, J = 7.9 Hz), 8.09 (1H, s), 12.65 (1H, brs). [α]_(D) ²⁷ = −114 (c0.30, EtOH)

TABLE 28 Ref. No Str. Chemical name P.D. 8-11

(3S*,4R*)-4-(7- fluorochroman- 6-yl)-2- oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, DMSO-d₆) δ 1.84-1.90 (2H, m), 2.67 (2H, t, J = 6.1Hz), 3.16 (1H, t, J = 9.2 Hz), 3.45 (1H, d, J = 10.4 Hz), 3.52 (1H, t, J= 8.9 Hz), 3.94 (1H, q, J = 9.4 Hz), 4.10 (2H, t, J = 5.2 Hz), 6.56 (1H,d, J = 12.2 Hz), 7.13 (1H, d, J = 8.6 Hz), 8.08 (1H, s), 12.67 (1H,brs). 8-12

(3S*,4S*)-4-(3- fluoro-5- methoxypyridin- 2-yl)- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.28 (1H, t, J = 8.9 Hz),3.60-3.66 (2H, m), 3.83 (3H, s), 4.21 (1H, q, J = 9.0 Hz), 7.44 (1H, dd,J = 11.6, 2.4 Hz), 8.06 (1H, s), 8.17 (1H, d, J = 2.4 Hz), 12.70 (1H,brs). 8-13

(3S*,4S*)-4-(5- methoxythiophen- 2-yl)-2- oxopyrrolidine-3- carboxylicacid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.18 (1H, t, J = 9.4 Hz), 3.30 (1H, d,J = 10.3 Hz), 3.55-3.59 (1H, m), 3.79 (3H, s), 3.91 (1H, q, J = 10.3),6.12 (1H, d, J = 4.2 Hz), 6.59 (1H, d, J = 4.2 Hz), 8.08 (1H, s), 12.78(1H, brs). 8-14

(3S*,4R*,5R*)-4- (4- methoxyphenyl)- 5-methyl- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 1.05 (3H, d, J = 6.1 Hz),3.16 (1H, dd, J = 11.5, 9.1 Hz), 3.49-3.58 (2H, m), 3.72 (3H, s), 6.88(2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 8.11 (1H, s), 12.54 (1H,s).

TABLE 29 Ref. No Str. Chemical name P.D. 8-15

(3S*,4R*,5S*)-4- (4- methoxyphenyl)- 5-methyl- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 0.66 (3H, d, J = 6.7 Hz),3.72 (3H, s), 3.77 (1H, d, J = 10.9 Hz), 3.81-3.89 (1H, m), 3.94 (1H,dd, J = 10.9, 7.3 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.20 (2H, d, J = 8.5Hz), 8.12 (1H, s), 12.61 (1H, s). 8-16

(3S*,4R*)-4-(4- methylthiophenyl)- 2-oxopyrrolidine- 3-carboxylic acid¹H-NMR (400 MHz, DMSO-d₆) δ 2.49 (3H, s), 3.22 (1H, t, J = 9.4 Hz), 3.50(1H, d, J = 9.7 Hz), 3.62 (1H, t, J = 8.8 Hz), 3.86 (1H, q, J = 9.5 Hz),7.26 (2H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 8.10 (1H, brs). 8-17

(3S*,4R*)-4-(4- ethyl-2,6- difluorophenyl)-2- oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 1.15 (3H, t, J = 7.6 Hz),2.59 (2H, q, J = 7.6 Hz), 3.27 (1H, t, J = 9.2 Hz), 3.46 (1H, d, J =10.4 Hz), 3.58 (1H, t, J = 9.2 Hz), 4.20 (1H, q, J = 9.4 Hz), 6.99 (2H,dd, J = 12.8, 3.1 Hz), 8.22 (1H, s), 12.81 (1H, brs). 8-18

(3R*,4S*)-4- phenyl-2- oxopyrrolidine- 3-carboxylic acid 1H-NMR (400MHz, CDCl₃) δ 3.47 (1H, t, J = 9.1Hz), 3.57 (1H, d, J = 10.3 Hz), 3.82(1H, t, J = 9.1 Hz), 4.05 (1H, q, J = 9.4 Hz), 6.71 (1H, s), 7.24-7.37(5H, m). 8-19

(+)-(3R*,4S*)- 4-(4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylic acid¹H-NMR (400 MHz, DMSO-d₆) δ 3.16 (1H, t, J = 9.4 Hz), 3.42 (1H, d, J =10.9 Hz), 3.55 (1H, t, J = 8.2 Hz), 3.72 (3H, s), 3.79 (1H, q, J = 9.5Hz), 6.88 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 8.03 (1H, s),12.54 (1H, brs). [α]_(D) ²⁵ = +99 (c 0.19, EtOH)

TABLE 30 Ref. No Str. Chemical name P.D. 8-20

(3R*,4S*)- methyl-4-(3- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, CDCl₃) δ 3.46 (1H, t, J = 9.4 Hz), 3.56 (1H, d, J= 9.7 Hz), 3.75-3.83 (1H, m), 3.79 (3H, s), 4.01 (1H, q, J = 9.4 Hz),6.58 (1H, s), 6.79-6.89 (3H, m), 7.26 (1H, t, J = 8.0 Hz). 8-21

(3R*,4S*)- methyl-4-(2- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, CDCl₃) δ 3.58 (1H, t, J = 9.1 Hz), 3.71 (1H, t, J= 9.1 Hz), 3.86 (3H, s), 3.98 (1H, d, J = 10.3 Hz), 4.06 (1H, t, J = 9.4Hz), 6.31 (1H, brs), 6.91 (1H, d, J = 8.6 Hz), 6.93-6.98 (1H, m),7.26-7.32 (2H, m). 8-22

(+)-(3R*,4S*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.25 (1H, t, J = 9.2 Hz),3.43 (1H, d, J = 10.4 Hz), 3.56 (1H, t, J = 9.2 Hz), 3.76 (3H, s), 4.14(1H, q, J = 9.4 Hz), 6.73-6.80 (2H, m), 8.20 (1H, s), 12.77 (1H, brs).[α]_(D) ²³ = +120 (c 0.10, EtOH) 8-23

(3R*,4S*,5S*)-4- (4- methoxyphenyl)- 5-methyl- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 1.05 (3H, d, J = 6.1 Hz),3.16 (1H, dd, J = 11.5, 9.1 Hz), 3.49-3.58 (2H, m), 3.72 (3H, s), 6.88(2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 8.11 (1H, s), 12.54 (1H,s). 8-24

(3R*,4S*,5R*)-4- (4- methoxyphenyl)- 5-methyl- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 0.66 (3H, d, J = 6.7 Hz),3.72 (3H, s), 3.77 (1H, d, J = 10.9 Hz), 3.81-3.89 (1H, m), 3.94 (1H,dd, J = 10.9, 7.3 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.20 (2H, d, J = 8.5Hz), 8.12 (1H, s), 12.61 (1H, s).

TABLE 31 Ref. No Str. Chemical name P.D. 8-25

(3R*,4R*)-4-(5- methoxythiophen- 2-yl)-2- oxopyrrolidine-3- carboxylicacid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.18 (1H, t, J = 9.4 Hz), 3.30 (1H, d,J = 10.3 Hz), 3.55-3.59 (1H, m), 3.79 (3H, s), 3.91 (1H, q, J = 10.3),6.12 (1H, d, J = 4.2 Hz), 6.59 (1H, d, J = 4.2 Hz), 8.08 (1H, s), 12.78(1H, brs). 8-26

(3R*,4S*)-4-(4- (difluoromethoxy) phenyl)-2- oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, CDCl₃) δ 3.46 (1H, t, J = 9.7 Hz),3.54 (1H, d, J = 9.7 Hz), 3.83 (1H, t, J = 9.4 Hz), 4.05 (1H, q, J = 9.4Hz), 6.50 (1H, t, J = 73.9 Hz), 6.80 (1H, s), 7.13 (2H, d, J = 9.1 Hz),7.31 (2H, d, J = 9.1 Hz). 8-27

(±)-trans-4-(4- methoxyphenyl)- 2-oxopyrrolidine- 3-carboxylic acid¹H-NMR (400 MHz, DMSO-d₆) δ 3.16 (1H, t, J = 9.4 Hz), 3.42 (1H, d, J =10.9 Hz), 3.55 (1H, t, J = 8.2 Hz), 3.72 (3H, s), 3.79 (1H, q, J = 9.5Hz), 6.88 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 8.03 (1H, s),12.54 (1H, brs). 8-28

(±)-trans-4-(4- methoxyphenyl)- 5,5-dimethyl- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 0.78 (3H, s), 1.21 (3H,s), 3.50 (1H, d, J = 12.1 Hz), 3.73 (3H, s), 3.98 (1H, d, J = 12.1 Hz),6.88 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 8.09 (1H, s), 12.50(1H, brs).

TABLE 32 Ref. No Str. Chemical name P.D. 8-29

(±)-trans-4-(4- methoxyphenyl)- 2-oxo-1-azaspiro [4.4]nonane-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 1.00-1.81 (8H, m), 3.69(1H, d, J = 11.6 Hz), 3.72 (3H, s), 3.88 (1H, d, J = 11.6 Hz), 6.88 (2H,d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 8.37 (1H, s), 12.48 (1H, brs).8-30

(±)-trans-4-(4- methoxyphenyl)- 2-oxo-1-azaspiro [4.5]decane-3-carboxylic acid ¹H-NMR (400 MHz, CDCl₃) δ 0.80-0.89 (1H, m), 0.94-1.09(1H, m), 1.16-1.37 (2H, m), 1.41-1.49 (2H, m), 1.56-1.82 (4H, m), 3.55(1H, d, J = 11.5 Hz), 3.81 (3H, s), 3.86 (1H, d, J = 11.5 Hz), 6.72 (1H,brs), 6.90 (2H, d, J = 9.1 Hz), 7.15 (2H, d, J = 9.1 Hz).

TABLE 33 Ref. No. Str. Chemical name P.D. 8-31

(3S*,4R*)-4-[4- (difluoromethoxy)- 2,6- difluorophenyl]-2-oxopyrrolidine- 3-carboxylic acid ¹H-NMR (400 MHz, CDCl₃) δ 3.58 (1H,t, J = 9.7 Hz), 3.69-3.74 (1H, m), 3.82 (1H, d, J = 10.9 Hz), 4.35 (1H,dt, J = 10.3, 9.7 Hz), 6.26 (1H, br), 6.51 (1H, t, J = 72.1 Hz),6.74-6.80 (2H, m). 8-32

(3S*,4R*)-4-(4- ethoxy-2,6- difluorophenyl)-2- oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 1.29 (3H, t, J = 6.3 Hz),3.24 (1H, t, J = 9.2 Hz), 3.42 (1H, d, J = 9.8 Hz), 3.56 (1H, t, J = 9.2Hz), 4.03 (2H, q, J = 6.3 Hz), 4.14 (1H, ddd, J = 9.8, 9.2, 9.2 Hz),6.74 (2H, d, J = 10.4 Hz), 8.19 (1H, s), 12.81 (1H, s). 8-33

(3S*,4R*)-4-[4- (dimethylamino)- 2,6- difluorophenyl]-2- oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 2.88 (6H, s), 3.21 (1H, t,J = 9.2 Hz), 3.37 (1H, d, J = 10.4 Hz), 3.50 (1H, t, J = 9.2 Hz), 4.08(1H, q, J = 9.4 Hz), 6.36 (2H, d, J = 12.8 Hz), 8.11 (1H, s), 12.75 (1H,s). 8-34

(3S*,4R*)-4-(6- fluorobenzofuran- 5-yl)-2- oxopyrrolidine- 3-carboxylicacid 1H-NMR (400 MHz, DMSO-d₆) δ 2.32 (1H, t, J = 9.1 Hz), 3.52 (1H, d,J = 9.2 Hz), 3.63 (1H, t, J = 9.1 Hz), 4.09-4.16 (1H, m), 6.95 (1H, d, J= 2.1 Hz), 7.56 (1H, d, J = 11.0 Hz), 7.71 (1H, d, J = 7.9 Hz), 8.00(1H, d, J = 2.1 Hz), 8.06 (1H, s), 12.78 (1H, brs) 8-35

(3S*,4R*)-4-(6- methoxypyridin-3- yl)-2- oxopyrrolidine- 3-carboxylicacid ¹H-NMR (400 MHz, CDCl₃) δ 3.43-3.51 (2H, m), 3.82 (1H, t, J = 9.2Hz), 3.93 (3H, s), 4.01 (1H, q, J = 9.4 Hz), 6.37 (1H, brs), 6.77 (1H,d, J = 8.6 Hz), 7.56 (1H, dd, J = 8.6, 2.4 Hz), 8.15 (1H, d, J = 2.4Hz).

TABLE 34 Ref. No. Str. Chemical name P.D. 8-36

(3S*,4R*)-4-(4- acetamide-2,6- difluorophenyl)- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 2.05 (3H, s), 3.26 (1H, t,J = 9.5 Hz), 3.44 (1H, d, J = 9.8 Hz), 3.57 (1H, t, J = 9.5 Hz), 4.16(1H, q, J = 9.5 Hz), 7.30 (2H, d, J = 11.0 Hz), 8.21 (1H, s), 10.30 (1H,s), 12.80 (1H, brs). 8-37

(3S*,4R*)-4-{4- [(tert- butoxycarbonyl) (methyl) amino]-2,6-difluorophenyl}- 2-oxopyrrolidine- 3-carboxylic acid ¹H-NMR (400 MHz,CDCl₃) δ 1.49 (9H, s), 3.25 (3H, s), 3.58 (1H, t, J = 9.5 Hz), 3.70 (1H,t, J = 9.2 Hz), 3.84 (1H, d, J = 11.0 Hz), 4.34 (1H, q, J = 9.8 Hz),6.16 (1H, brs), 6.94 (2H, d, J = 10.4 Hz). 8-38

(3S*,4R*)-4-(4,6- difluoro-2,3- dihydrobenzofuran- 5-yl)-2-oxopyrrolidine- 3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 3.17-3.26(3H, m), 3.42 (1H, d, J = 10.4 Hz), 3.54 (1H, t, J = 9.2 Hz), 4.14 (1H,q, J = 9.6 Hz), 4.63 (2H, t, J = 8.6 Hz), 6.64 (1H, d, J = 11.0 Hz),8.19 (1H, s), 12.53 (1H, brs). 8-39

(3S*,4R*)-4-(6- fluoro-2,3-dihydro- 1H-inden-5-yl)- 2-oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, DMSO-d₆) δ 1.97-2.04 (2H, m),2.76-2.84 (4H, m), 3.18 (1H, t, J = 9.2 Hz), 3.47 (1H, d, J = 9.8 Hz),3.55 (1H, t, J = 8.6 Hz), 3.98-4.05 (1H, m), 7.03 (1H, d, J = 11.0 Hz),7.28 (1H, d, J = 7.3 Hz), 8.08 (1H, s), 12.71 (1H, brs). 8-40

(3S*,4R*)-4-(1- benzyl-6- fluoroindolin- 5-yl)-2- oxopyrrolidine-3-carboxylic acid ¹H-NMR (400 MHz, CDCl₃) δ 2.93-2.97 (2H, m), 3.43-3.51(3H, m), 3.68-3.78 (2H, m), 3.97 (1H, q, J = 9.2 Hz), 4.26 (2H, s), 6.15(1H, br), 6.28 (1H, d, J = 12.2 Hz), 7.01 (1H, d, J = 6.7 Hz), 7.30-7.38(5H, m).

TABLE 35 Ref. No. Str. Chemical name P.D. 8-41

(3S*,4R*)-4-(3,5- difluoropyridin- 4-yl)-2- oxopyrrolidine- 3-carboxylicacid 1H-NMR (400 MHz, DMSO-d₆) δ 3.28 (1H, t, J = 9.2 Hz), 3.43 (1H, d,J = 9.2 Hz), 3.64 (1H, t, J = 9.5 Hz), 4.30 (1H, q, J = 8.8 Hz), 8.18(1H, s), 8.51 (2H, s), 13.00 (1H, brs).

(3S*,4R*)-4-(6-Fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid

A 2 mol/L sodium hydroxide aqueous solution (0.44 mL) was added to asolution of(3S*,4R*)-4-{1-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-inden-5-yl}-2-oxopyrrolidine-3-carboxylicacid methyl ester (180 mg) in methanol (0.88 mL) to produce a reactionsolution. The reaction solution was stirred at 60° C. for 2 hours. A 1mol/L hydrochloric acid was added to the reaction solution to make thereaction solution acidic (pH: 1), and the reaction solution was stirredat room temperature for 1 hour, and extracted with ethyl acetate. Theorganic layer was washed with water and a brine successively, and driedover anhydrous sodium sulfate. The solvent was removed, and the crudeproduct was washed with a mixed solution of ethyl acetate and methanolat a ratio of 6:1, to obtain the title compound as a white solid (110mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 1.74-1.81 (1H, m), 2.29-2.36 (1H, m),2.61-2.69 (1H, m), 2.81-2.87 (1H, m), 3.19 (1H, t, J=9.2 Hz), 3.49 (1H,d, J=10.4 Hz), 3.56 (1H, t, J=9.2 Hz), 4.04 (1H, q, J=9.2 Hz), 4.99 (1H,q, J=6.7 Hz), 5.32 (1H, d, J=5.5 Hz), 7.06 (1H, d, J=10.4 Hz), 7.30 (1H,d, J=7.3 Hz), 8.11 (1H, s), 12.69 (1H, brs).

Reference Example 9-1

(4R*)-3-Chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester

Sulfuryl chloride (200 μL) was added to a solution of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester (250 mg) in tetrahydrofuran (5 mL) under an argonatmosphere to produce a reaction solution. The reaction solution wasstirred at room temperature for 2 hours. A saturated aqueous sodiumhydrogen carbonate solution was added to the reaction solution underice-cooling, and the reaction solution was extracted with ethyl acetate.The organic layer was washed with water and a brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (ethyl acetate:hexane=9:1 followed by ethyl acetate), toobtain (4R*)-3-chloro-4-(4-methoxyphenyl)₂-oxopyrrolidine-3-carboxylicacid methyl ester as an intermediate compound.

To a solution of the obtained(4R*)-3-chloro-4-(4-methoxyphenyl)₂-oxopyrrolidine-3-carboxylic acidmethyl ester (222 mg) in N,N-dimethylformamide (3.4 mL), sodium hydride(56 mg, 60% in oil) was added under ice-cooling to produce a reactionsolution. The reaction solution was stirred for 5 minutes, theniodomethane (97 μL) was added, and the reaction solution was stirred atroom temperature for 1 hour. A 1 mol/L hydrochloric acid was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and a brine successively, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was then purified by silica gel columnchromatography (ethyl acetate:hexane=9:1 followed by ethyl acetate), toobtain the title compound as a white solid (184 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.07 (3H, s), 3.50 (3H, s), 3.61-3.65 (1H, m),3.80 (3H, s), 3.88-3.99 (2H, m), 6.88 (2H, d, J=8.5 Hz), 7.23 (2H, d,J=8.5 Hz).

Reference Example 9-2

(4S*)-3-Chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester

The same method as in Reference Example 9-1 was performed using(+)-(3R*,4S*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.07 (3H, s), 3.50 (3H, s), 3.61-3.65 (1H, m),3.80 (3H, s), 3.88-3.99 (2H, m), 6.88 (2H, d, J=8.5 Hz), 7.23 (2H, d,J=8.5 Hz).

Reference Example 9-3

(+)-3-Chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester

The same method as in Reference Example 9-1 was performed using(±)-trans-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid methylester in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.07 (3H, s), 3.50 (3H, s), 3.61-3.65 (1H, m),3.80 (3H, s), 3.88-3.99 (2H, m), 6.88 (2H, d, J=8.5 Hz), 7.23 (2H, d,J=8.5 Hz).

Reference Example 10-1

(3S*,4R*)-4-(4-Methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid

Metal zinc (595 mg) and acetic acid (0.3 mL) were added to a solution of(4R*)-3-chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester (184 mg) in methanol (11 mL) to produce a reactionsolution. The reaction solution was stirred at room temperature for 1hour. The reaction solution was filtered over Celite to remove theinsoluble, and the solvent was removed under reduced pressure. Asaturated aqueous sodium hydrogen carbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The organiclayer was washed with a 1 mol/L hydrochloric acid and a brine, and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane followed by ethyl acetate:hexane=1:1), to obtain(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester as an intermediate compound.

A 2 mol/L sodium hydroxide aqueous solution (0.57 mL) was added to asolution of the obtained(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester (130 mg) in methanol (2.8 mL) to produce a reactionsolution. The reaction solution was stirred at 70° C. for 1 hour. A1mol/L hydrochloric acid was added to the reaction solution to make thereaction solution acidic (pH: 1), and the mixture was extracted withethyl acetate. The organic layer was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the crude product was washed withethyl acetate-diisopropyl ether, to obtain the title compound as a whitesolid (133 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.78 (3H, s), 3.27-3.34 (1H, m), 3.45 (1H,d, J=10.3 Hz), 3.65 (1H, t, J=8.8 Hz), 3.70-3.77 (1H, m), 3.72 (3H, s),6.89 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 12.70 (1H, brs).

Reference Example 10-2

(3R*,4S*)-4-(4-Methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid

The same method as in Reference Example 10-1 was performed using(4S*)-3-chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester in place of(4R*)-3-chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.78 (3H, s), 3.27-3.34 (1H, m), 3.45 (1H,d, J=10.3 Hz), 3.65 (1H, t, J=8.8 Hz), 3.70-3.77 (1H, m), 3.72 (3H, s),6.89 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 12.70 (1H, brs).

Reference Example 10-3

(±)-trans-4-(4-Methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid

The same method as in Reference Example 10-1 was performed using(±)-3-Chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester in place of(4R*)-3-chloro-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylicacid methyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.78 (3H, s), 3.27-3.34 (1H, m), 3.45 (1H,d, J=10.3 Hz), 3.65 (1H, t, J=8.8 Hz), 3.70-3.77 (1H, m), 3.72 (3H, s),6.89 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 12.70 (1H, brs).

Reference Example 11-1

(−)-[(3S*,4R*)-4-(4-Methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidbenzyl ester

Triethylamine (3.95 mL) and diphenylphosphoryl azide (6.2 mL) were addedto a solution of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid(6.04 g) in toluene (128 mL) to produce a reaction solution. Thereaction solution was stirred at room temperature for 4.5 hours. Thereaction temperature of the reaction solution was heated up to 80° C.,and the reaction solution was then stirred for 30 minutes. To thereaction solution, benzyl alcohol (13.3 mL) was added, and the reactionsolution was stirred at 120° C. for 5 hours. The reaction solution wasconcentrated under reduced pressure, and the residue was then purifiedby silica gel column chromatography (ethyl acetate followed by ethylacetate:methanol=10:1), to obtain the title compound as a white solid(6.3 g).

¹H-NMR (400 MHz, CDCl₃) δ 3.36 (1H, t, J=9.1 Hz), 3.49-3.70 (2H, m),3.80 (3H, s), 4.42 (1H, dd, J=11.5, 8.5 Hz), 5.07 (2H, s), 5.16 (1H,brs), 5.98 (1H, brs), 6.89 (2H, d, J=7.9 Hz), 7.22 (2H, d, J=7.9 Hz),7.20-7.40 (5H, m).

[α]_(D) ²⁷=−79 (c 0.17, EtOH)

Reference Example 11-2

(+)-[(3R*,4S*)-4-(4-Methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidbenzyl ester

The same method as in Reference Example 11-1 was performed using(+)-(3R*,4S*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid inplace of (−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.36 (1H, t, J=9.1 Hz), 3.49-3.70 (2H, m),3.80 (3H, s), 4.42 (1H, dd, J=11.5, 8.5 Hz), 5.07 (2H, s), 5.16 (1H,brs), 5.98 (1H, brs), 6.89 (2H, d, J=7.9 Hz), 7.22 (2H, d, J=7.9 Hz),7.20-7.40 (5H, m).

[α]_(D) ²⁷=+81 (c 0.16, EtOH)

Reference Example 12-1

(−)-[(3S*,4R*)-4-(2-Fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester

Triethylamine (1.0 mL) and diphenylphosphoryl azide (1.5 mL) were addedto a solution of(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid (1.6 g) in a mixture of toluene (63 mL) and acetonitrile (10 mL) toproduce a reaction solution. The reaction solution was stirred at roomtemperature for 3 hours. The reaction temperature of the reactionsolution was heated up to 80° C., and the reaction solution was thenstirred for 30 minutes. To the reaction solution, benzyl alcohol (3.3mL) was added, and the reaction solution was stirred at 110° C. for 3.5hours. Ethyl acetate was added to the reaction solution, and the mixturewas washed with a 1 mol/L hydrochloric acid, water, and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (hexane:ethyl acetate=4:1 followed byethyl acetate:methanol=10:1), to obtain the title compound as a whitesolid (767 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.40 (1H, t, J=8.6 Hz), 3.63-3.82 (2H, m),3.79 (3H, s), 4.62 (1H, dd, J=11.0, 8.6 Hz), 5.07 (2H, brs), 5.16 (1H,brs), 6.01 (1H, brs), 6.58-6.73 (2H, m), 7.25-7.33 (6H, m).

[α]_(D) ²⁴=−134 (c 0.16, EtOH)

The same method as in Reference Example 12-1 was performed using acorresponding carboxylic acid substance to obtain the followingReference Examples 12-2 to 12-4. The structures and spectral datathereof are shown in Table 36.

TABLE 36 Ref. No Str. Chemical name P.D. 12-2

(−)-[(3S*,4R*)- 4-(2,6-difluoro- 4- methoxyphenyl)- 2-oxopyrrolidin-3-yl] carbamic acid benzyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.48-3.62(2H, m), 3.79 (3H, s), 3.80-3.96 (1H, m), 4.67-4.75 (1H, m), 5.05 (2H,s), 5.38 (1H, brd, J = 8.0 Hz), 6.42-6.53 (2H, m), 6.60 (1H, s),7.26-7.36 (5H, m). [α]_(D) ²⁴ = −107 (c 0.10, EtOH) 12-3

(−)-[(3S*,4R*)- 4-(6-fluoro-2,3- dihydrobenzofuran- 5-yl)-2-oxopyrrolidin-3-yl] carbamic acid benzyl ester ¹H-NMR (400 MHz, CDCl₃) δ3.05-3.25 (2H, m), 3.37 (1H, t, J = 9.2 Hz), 3.55-3.80 (2H, m),4.50-4.65 (3H, m) 5.04-5.14 (3H, m), 5.83 (1H, s), 6.50 (1H, d, J = 10.4Hz), 7.10-7.22 (1H, m), 7.26-40 (5H, m). [α]_(D) ²⁹ = −185 (c 0.16,EtOH) 12-4

(−)-[(3S*,4R*)- 4-(3-fluoro-5- methoxypyridin- 2-yl)-2- oxopyrrolidin-3-yl]carbamic acid benzyl ester ¹H-NMR (400 MHz, DMSO-d₆) δ 3.29-3.36 (1H,m), 3.45 (1H, t, J = 8.9 Hz), 3.83 (3H, s), 3.91-3.98 (1H, m), 4.38 (1H,t, J = 9.8 Hz), 4.93 (1H, d, J = 12.8 Hz), 4.98 (1H, d, J = 12.8 Hz),7.27-7.35 (5H, m), 7.40 (1H, dd, J = 11.6, 1.8 Hz), 7.61 (1H, d, J = 8.6Hz), 7.94 (1H, s), 8.20 (1H, d, J = 1.8 Hz). [a]_(D) ²⁹ = −126 (c 0.12,EtOH)

Reference Example 13-1

(−)-(3S*,4R*)-3-Amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one

10% Palladium on carbon (81 mg) was added to a solution of(−)-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester (811 mg) in ethanol (30 mL) to produce a reactionsolution. The reaction solution was stirred under a hydrogen atmospherefor 2 hours. The reaction solution was filtered over Celite, and thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=1:1 followed byethyl acetate:methanol=9:1), to obtain the title compound as a whitesolid (520 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.22 (1H, t, J=8.0 Hz), 3.34-3.43 (2H, m),3.47 (1H, d, J=9.8 Hz), 3.76 (3H, s), 6.74 (2H, d, J=11.0 Hz), 7.88 (1H,s).

[α]_(D) ²⁴=−90 (c 0.11, EtOH)

Reference Example 13-2

(3S*,4R*)-3-Amino-4-(3-fluoro-5-methoxypyridin-2-yl)pyrrolidin-2-one

The same method as in Reference Example 13-1 was performed using(−)-[(3S*,4R*)-4-(3-fluoro-5-methoxypyridin-2-yl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester in place of(−)-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.84 (2H, s), 3.22 (1H, t, J=9.2 Hz), 3.40(1H, t, J=8.6 Hz), 3.51-3.58 (1H, m), 3.61 (1H, d, J=9.8 Hz), 3.83 (3H,s), 7.41 (1H, dd, J=11.9, 1.4 Hz), 7.77 (1H, s), 8.19 (1H, d, J=1.4 Hz).

Reference Example 14-1

(−)-[(3S*,4R*)-4-(4-Methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidtert-butyl ester

Triethylamine (2.64 mL) and diphenylphosphoryl azide (4.07 mL) wereadded to a solution of (−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (4.05 g)in toluene (80 mL) to produce a first reaction solution. The firstreaction solution was stirred at room temperature for 5 hours. Thereaction temperature of the first reaction solution was heated up to 80°C., and the first reaction solution was then stirred for 20 minutes.After that, the first reaction solution was concentrated under reducedpressure. To the residue, dioxane (50 mL) and a 1 mol/L hydrochloricacid (50 mL) were added to produce a second reaction solution. Thesecond reaction solution was stirred at room temperature for 30 minutes.The second reaction solution was concentrated under reduced pressure,water (40 mL) was added, and the mixture was washed with diethyl ether.The aqueous layer was concentrated under reduced pressure, and methanol(77 mL), triethylamine (10 mL), and di-tert-butyl dicarbonate (4.28 g)were added to the residue to produce a third reaction solution. Thethird reaction solution was stirred at room temperature for 3 hours. Thethird reaction solution was concentrated under reduced pressure, waterwas added to the residue, and the mixture was extracted with ethylacetate. The organic layer was washed with a brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the crude product was washed with chloroform, to obtainthe title compound as a white solid (2.97 g).

¹H-NMR (400 MHz, CDCl₃) δ 1.33 (9H, s), 3.10-3.17 (1H, m), 3.37-3.45(2H, m), 3.71 (3H, s), 4.12 (1H, t, J=7.0 Hz), 6.87 (2H, d, J=8.6 Hz),7.07 (1H, d, J=9.2 Hz), 7.23 (2H, d, J=8.6 Hz), 7.83 (1H, brs).

[α]_(D) ²⁷=−64 (c 0.14, EtOH)

Reference Example 14-2

(+)-trans-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidtert-butyl ester

The same method as in Reference Example 14-1 was performed using(±)-trans-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid inplace of (−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.33 (9H, s), 3.10-3.17 (1H, m), 3.37-3.45(2H, m), 3.71 (3H, s), 4.12 (1H, t, J=7.0 Hz), 6.87 (2H, d, J=8.6 Hz),7.07 (1H, d, J=9.2 Hz), 7.23 (2H, d, J=8.6 Hz), 7.83 (1H, brs).

Reference Example 15-1

[(3S*,4R*)-1-Ethyl-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carb amicacid tert-butyl ester

A solution of(−)-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidtert-butyl ester (181 mg) in N,N-dimethylformamide (0.9 mL) and asolution of ethyl iodide (50 μL) in tetrahydrofuran (1.2 mL) were addedto a solution of sodium hydride (42 mg, 60% in oil) in tetrahydrofuran(2.3 mL) under cooling, and the mixture was stirred at room temperaturefor 4 hours. Water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed with abrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the residue was then purified by silica gelcolumn chromatography (ethyl acetate:hexane=4:1), to obtain the titlecompound as a white solid (65 mg).

¹H-NMR (400 MHz, CDCl₃) 1.17 (3H, t, J=7.4 Hz), 1.38 (9H, s), 3.31-3.60(5H, m), 3.80 (3H, s), 4.30 (1H, t, J=9.2 Hz), 4.84 (1H, brs), 6.89 (2H,d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz).

Reference Example 15-2

2-{(3S*,4R*)-3-[(tert-Butoxycarbonyl)amino]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid ethyl ester

The same method as in Reference Example 15-1 was performed usingbromoacetic acid ethyl ester in place of ethyl iodide as an alkylatingagent to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) 1.30 (3H, t, J=7.3 Hz), 1.39 (9H, s), 3.50-3.65(3H, m), 3.80 (3H, s), 3.96 (1H, d, J=17.8 Hz), 4.21 (2H, q, J=7.3 Hz),4.31 (1H, d, J=17.8 Hz), 4.34 (1H, t, J=8.6 Hz), 4.87 (1H, brs), 6.89(2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz).

Reference Example 15-3

2-{(3S*,4R*)-3-[(tert-Butoxycarbonyl)amino]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid ethyl ester

The same method as in Reference Example 15-1 was performed using2-bromopropionic acid ethyl ester in place of ethyl iodide as analkylating agent to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.27-1.48 (15H, m), 3.29-3.80 (3H, m), 3.80(3H, s), 4.15-4.31 (3H, m), 4.57 (0.5H, brs), 4.80 (0.5H, brs),4.88-4.99 (1H, m), 6.88 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=9.2 Hz).

Reference Example 16-1

(±)-trans-({1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamic acid tert-butyl ester

To a solution of(±)-trans-(4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamic acidtert-butyl ester (1.03 g) and (2-bromoethoxy) (tert-butyl)dimethylsilane(1.44 mL) in N,N-dimethylformamide (10 mL), sodium hydride (141 mg, 60%in oil) was added in several portions under cooling to produce areaction solution. The reaction solution was stirred at room temperaturefor 2 hours. A saturated aqueous ammonium chloride solution was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and a brine successively, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=3:1), to obtain the title compoundas a colorless oil (1.1 g).

¹H-NMR (400 MHz, CDCl₃) δ 0.06 (6H, s), 0.89 (9H, s), 1.37 (9H, s),3.30-3.47 (2H, m), 3.52 (1H, t, J=9.7 Hz), 3.57-3.64 (1H, m), 3.71 (1H,t, J=9.1 Hz), 3.76-3.80 (2H, m), 3.80 (3H, s), 4.33 (1H, t, J=9.4 Hz),4.81 (1H, brs), 6.89 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz).

Reference Example 17-1

2-{(3S*,4R*)-3-[(tert-Butoxycarbonyl)amino]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionicacid ethyl ester

Lithium hexamethyldisilazide (3.8 mL, 1.3 mol/L tetrahydrofuransolution) was added to a solution of2-{(3S*,4R*)-3-[(tert-butoxycarbonyl)amino]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid ethyl ester (384 mg) in tetrahydrofran (10 mL) at −78° C., toproduce a reaction solution. The reaction solution was stirred for 30minutes. Methyl iodide (0.31 mL) was added to the reaction solution, thetemperature was heated up to room temperature, and the reaction solutionwas stirred for 24 hours. A 10% citric acid aqueous solution was addedto the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate:hexane=4:1 followed byethyl acetate), to obtain the title compound as a white solid (222 mg).

¹H-NMR (400 MHz, CDCl₃) δ 1.29 (3H, t, J=7.4 Hz), 1.36 (9H, s), 1.50(3H, s), 1.57 (3H, s), 3.34-3.42 (2H, m), 3.70-3.77 (1H, m), 3.80 (3H,s), 4.20 (2H, q, J=7.4 Hz), 4.36 (1H, t, J=10.4 Hz), 4.83 (1H, brs),6.89 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz).

Reference Example 17-2

2-((3S*,4R*)-3-{[(Benzyloxy)carbonyl]amino}-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-1-yl)-2-methylpropanoicacid ethyl ester

The same method as in Reference Example 17-1 was performed using2-((3S*,4R*)-3-{[(benzyloxy)carbonyl]amino}-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-1-yl)aceticacid ethyl ester in place of(−)-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidtert-butyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.28 (3H, t, J=7.0 Hz), 1.50 (3H, s), 1.56(3H, s), 3.10-3.22 (2H, m), 3.37 (1H, t, J=9.2 Hz), 3.52-3.66 (1H, m),3.69-3.80 (1H, m), 4.20 (2H, q, J=7.0 Hz), 4.57-4.65 (1H, m), 4.60 (2H,t, J=8.6 Hz), 5.00-5.13 (3H, m), 6.51 (1H, d, J=10.4 Hz), 7.17-7.23 (1H,m), 7.28-7.36 (5H, m).

Reference Example 18-1

[(3S*,4R*)-1-(1-Hydroxy-2-methylpropan-2-yl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid tert-butyl ester

Lithiumborohydride (1.5 mL, 3 mol/L tetrahydrofuran solution) was addedto a solution of2-{(3S*,4R*)-3-[(tert-butoxycarbonyl)amino]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionicacid ethyl ester (421 mg) in tetrahydrofran (10 mL) under ice-cooling,to produce a reaction solution. The reaction solution was stirred atroom temperature for 2 hours. A 10% citric acid aqueous solution wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate:hexane=4:1), to obtainthe title compound as a white solid (88 mg).

¹H-NMR (400 MHz, CDCl₃) δ 1.30 (3H, s), 1.31 (3H, s), 1.40 (9H, s),3.28-3.39 (2H, m), 3.65-3.75 (2H, m), 3.81 (3H, s), 3.92 (1H, brs), 4.32(1H, t, J=9.2 Hz), 4.57 (1H, brs), 4.86 (1H, brs), 6.89 (2H, d, J=8.6Hz), 7.22 (2H, d, J=8.6 Hz).

Reference Example 19-1

[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester

Potassium tert-butoxide (60 mg) and iodomethane (33 μL) were added to asolution of(−)-[3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester (200 mg) in N,N-dimethylformamide (5.3 mL) underice-cooling, to produce a reaction solution. The reaction solution wasstirred for 2 hours. A saturated aqueous ammonium chloride solution wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with a brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=4:1 followed by ethyl acetate), toobtain the title compound as a white solid (100 mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.95 (3H, s), 3.40-3.62 (2H, m), 3.77 (3H, s),3.80-3.84 (1H, m), 4.57-4.67 (1H, m), 5.04 (2H s), 5.20 (1H, brs),6.40-6.51 (2H, m), 7.26-7.33 (5H, m).

The same method as in Reference Example 19-1 was performed using acorresponding alkylating agent to obtain the following ReferenceExamples 19-2 to 19-9. The structures and spectral data thereof areshown in Tables 37 to 39.

TABLE 37 Ref. No Str. Chemical name P.D. 19-2

[(3S*,4R*)-4-(2,6- difluoro-4-meth- oxyphenyl)-2-oxo-1-propylpyrrolidin- 3-yl]carbamic acid benzyl ester ¹H-NMR (400 MHz,CDCl₃) δ 0.94 (3H, t, J = 7.3 Hz), 1.52-1.65 (2H, m), 3.20- 3.35 (1H,m), 3.36-3.63 (3H, m), 3.65-3.85 (1H, m), 3.77 (3H, s), 4.63-4.70 (1H,m), 5.03 (2H, s), 5.21 (1H, brs), 6.42-6.52 (2H, m), 7.25-7.35 (5H, m).19-3

[(3S*,4R*)-1- benzyl-4-(2,6- difluoro-4-meth- oxyphenyl)-2-oxo-pyrrolidin-3-yl] carbamic acid benzyl ester ¹H-NMR (400 MHz, CDCl₃) δ3.30-3.47 (2H, m), 3.73- 3.82 (1H, m), 3.75 (3H, s), 4.50 (1H, d, J =14.7 Hz), 4.61 (1H, d, J = 15.3 Hz), 4.70 (1H, t, J = 9.8 Hz), 5.04 (2H,d, J = 11.2 Hz), 5.27 (1H, brs), 6.42 (2H, d, J = 10.4 Hz), 7.26-7.37(10H, m). 19-4

[(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)- 2-oxo-1-(pyridin-3-ylmethyl)- pyrrolidin-3-yl] carbamic acid benzyl ester ¹H-NMR (400MHz, CDCl₃) δ 3.56 (2H, t, J = 8.0 Hz), 3.76-3.95 (4H, m), 4.61-4.79(3H, m), 5.03-5.08 (2H, m), 5.26 (1H, brs), 6.42 (2H, d, J = 9.8 Hz),7.20-7.31 (7H, m), 7.71 (1H, brs), 8.54 (1H, d, J = 4.9 Hz).

TABLE 38 Ref. No Str. Chemical name P.D. 19-5

2-((3S*,4R*)-3- {[benzyloxy)carbonyl]- amino}-4-(2,6-difluoro-4-methoxyphenyl)-2- oxopyrrolidin-1-yl) acetic acid ethyl ester ¹H-NMR(400 MHz, DMSO- d₆) δ 1.30 (3H, t, J = 7.3 Hz), 3.47-3.60 (1H, m),3.70-3.95 (2H, m), 3.78 (3H, s), 4.06 (1H, d, J = 17.8 Hz), 4.22 (2H, q,J = 7.3 Hz), 4.22-4.27 (1H, d, J = 17.8 Hz) 4.76 (1H, t, J = 9.2 Hz),4.98-5.10 (2H, m), 5.19 (1H, brs), 6.40-6.55 (2H, m), 7.26-2.36 (5H, m).19-6

2-((3S*,4R*)-3- {[benzyloxy)carbonyl]- amino}-4-(6-fluoro-2,3-dihydrobenzofuran- 5-yl)-2-oxopyrrolidin- 1-yl)acetic acid ethyl ester¹H-NMR (400 MHz, CDCl₃) δ 1.29 (3H, t, J = 7.1 Hz), 3.09-3.23 (2H, m),3.49-3.59 (1H, m), 3.59-3.76 (2H, m), 3.98 (1H, d, J = 17.7 Hz),4.11-4.31 (1H, m), 4.21 (2H, q, J = 7.1 Hz), 4.58-4.66 (3H, m),5.00-5.20 (1H, m), 5.08 (2H, s), 6.51 (1H, d, J = 11.0 Hz), 7.10-7.20(1H, m), 7.26- 7.36 (5H, m). 19-7

[(3S*,4R*)-1-cyclo- propylmethyl)-4-(6- fluoro-2,3-dihydro-benzofuran-5-yl)-2- oxopyrrolidin-3-yl] carbamic acid benzyl ester¹H-NMR (400 MHz, CDCl₃) δ 0.22-0.26 (2H, m), 0.52- 0.57 (2H, m),0.85-0.99 (1H, m), 3.09 (1H, dd, J = 13.9, 7.3 Hz), 3.10-3.22 (2H, m),3.37 (1H, dd, J = 13.9, 7.0 Hz), 3.43 (1H, t, J = 9.2 Hz), 3.55-3.77(2H, m), 4.58-4.64 (3H, m), 5.02-5.17 (3H, m), 6.52 (1H, d, J = 11.0Hz), 7.10-7.22 (1H, m), 7.28- 7.36 (5H, m).

TABLE 39 Ref. No Str. Chemical name P.D. 19-8

[(3S*,4R*)-1-(cyano- methyl)-4-(6-fluoro- 2,3-dihydrobenzo-furan-5-yl)-2-oxo- pyrrolidin-3-yl] carbamic acid benzyl ester ¹H-NMR(400 MHz, CDCl₃) δ 3.14-3.19 (2H, m), 3.48- 3.54 (1H, m), 3.70-3.80 (2H,m), 4.23-4.27 (1H, m), 4.44-4.52 (2H, m), 4.62 (2H, t, J = 9.1 Hz),5.06- 5.13 (3H, m), 6.52-6.54 (1H, m), 7.09-7.12 (1H, m,), 7.32-7.34(5H, m). 19-9

{(3S*,4R*)-4-(6- fluoro-2,3-dihydro- benzofuran-5-yl)-1-[(5-methyl-1,3,4- oxadiazol-2-yl)- methyl]-2-oxo- pyrrolidin-3-yl}carbamic acid benzyl ester ¹H-NMR (400 MHz, CDCl₃) δ 2.53 (3H, s),3.12-3.16 (2H, m), 3.43-3.47 (1H, m), 3.67-3.73 (2H, m), 4.57-4.66 (4H,m), 4.80- 4.84 (1H, m), 5.07 (2H, s), 5.42 (1H, br), 6.59 (1H, d, J =10.9 Hz), 7.13-7.14 (1H, m), 7.27-7.32 (5H, m).

Reference Example 19-10

{(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-[(methylthio)methyl]-2-oxopyrrolidin-3-yl}carbamicacid benzyl ester

Chloromethyl methyl sulfide (73 μL), tetrabutylammonium iodide (12 mg),and potassium tert-butoxide (86 mg) were added to a solution of[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester (120 mg) in N,N-dimethylformamide (3.2 mL) underice-cooling, to produce a reaction solution. The reaction solution wasstirred at room temperature for 4 hours. A saturated aqueous ammoniumchloride solution was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and a brine successively, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue was thenpurified by silica gel column chromatography (hexane:ethyl acetate=9:1followed by 1:1), to obtain the title compound (56 mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.14 (3H, brs), 3.60-3.69 (2H, m), 3.78 (3H,s), 3.85-3.93 (1H, m), 4.49 (2H, s), 4.58-4.66 (1H, m), 5.03 (1H, d,J=12.2 Hz), 5.09 (1H, d, J=12.2 Hz), 5.20 (1H, brs), 6.48 (2H, d, J=9.8Hz), 7.28-7.34 (5H, m).

Reference Example 19-11

[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxo-1-(sulfamoylmethyl)pyrrolidin-3-yl]carbamicacid benzyl ester The same method as in Reference Example 19-10 wasperformed using 1-chloromethanesulfonamide in place of chloromethylmethysulfide to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.60-3.70 (1H, m), 3.78 (3H, s), 4.21-4.24(4H, m), 5.05 (1H, d, J=12.2 Hz), 5.11-5.17 (2H, m), 5.29 (2H, brs),5.63 (1H, brs), 6.48 (2H, d, J=10.4 Hz), 7.29-7.38 (5H, m).

Reference Example 19-12

{(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-[(methylsulfonyl)methyl]-2-oxopyrrolidin-3-yl}carbamicacid benzyl ester

Meta-chloroperoxybenzoic acid (79 mg) was added to a solution of{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-[(methylthio)methyl]-2-oxopyrrolidin-3-yl}carbamicacid benzyl ester (56 mg) in dichloromethane (2.2 mL) under ice-coolingto produce a reaction solution. The reaction solution was stirred atroom temperature for 4 hours. A saturated aqueous sodium sulfitesolution was added to the reaction solution, and the mixture wasextracted with dichloromethane. The organic layer was washed with asaturated sodium hydrogen carbonate solution and a brine successively,and dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=9:1 followed by ethyl acetate), toobtain the title compound (57 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.01 (3H, brs), 3.75-3.81 (4H, m), 4.06-4.22(2H, m), 4.30-4.41 (2H, m), 4.86 (1H, d, J=14.7 Hz), 5.04 (1H, d, J=12.2Hz), 5.12 (1H, d, J=12.2 Hz), 5.29 (1H, d, J=4.2 Hz), 6.48 (2H, d,J=10.4 Hz), 7.28-7.37 (5H, m).

Reference Example 20-1

((3S*,4R*)-1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamic acid benzyl ester

To a solution of(−)-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamicacid benzyl ester (346 mg) and (2-bromoethoxy)(tert-butyl)dimethylsilane (2.0 mL) in N,N-dimethylformamide (9.7 mL),potassium tert-butoxide (216 mg) was added in several portions toproduce a reaction solution. The reaction solution was stirred at roomtemperature for 15 hours. A saturated aqueous ammonium chloride solutionwas added to the reaction solution, and the mixture was extracted withethyl acetate. The organic layer was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (hexane:ethyl acetate=9:1 followed byethyl acetate), to obtain the title compound as a colorless oil (204mg).

¹H-NMR (400 MHz, CDCl₃) δ0.06 (6H, s), 0.88 (9H, s), 3.32-3.41 (1H, m),3.48-3.63 (3H, m), 3.75-3.81 (6H, m), 4.64 (1H, dd, J=11.0, 8.0 Hz),5.00-5.15 (3H, m), 6.58-6.73 (2H, m), 7.24-7.32 (6H, m).

The same method as in Reference Example 20-1 was performed using acorresponding 2-oxopyrrolidine substance to obtain the followingReference Examples 20-2 to 20-4.

The structures and spectral data thereof are shown in Table 40.

TABLE 40 Ref. No Str. Chemical name P.D. 20-2

((3S*,4R*)-1-{2-[(tert- butyldimethylsilyl)- oxy]ethyl}-4-(2,6-difluoro-4-methoxy- phenyl)-2-oxopyrrol- idin-3-yl)carbamic acid benzylester ¹H-NMR (400 MHz, CDCl₃) δ 0.00 (6H, s), 0.82 (9H, s), 3.24-3.33(1H, m), 3.48- 3.62 (3H, m), 3.66-3.75 (6H, m), 4.64-4.70 (1H, m), 4.97(2H, s), 5.16 (1H, brs), 6.35-6.45 (2H, m), 7.21-7.27 (5H, m). 20-3

(1-{2-[(tert-butyl- dimethylsilyl)oxy]- ethyl}-4-(4-methoxy-phenyl)-2-oxopyrrol- idin-3-yl)carbamic acid tert-butyl ester ¹H-NMR(400 MHz, CDCl₃) δ 0.08 (6H, s), 0.89 (9H, s), 1.36 (9H, s), 3.48 (1H,dt, J = 14.0, 4.9 Hz), 3.89 (1H, dt, J = 14.0, 4.9 Hz), 3.66 (1H, d, J =10.4 Hz), 3.79 (3H, s), 3.84 (2H, t, J = 4.9 Hz), 3.92 (1H, dd, J =10.4, 6.1 Hz), 4.57-4.61 (2H, m), 6.80 (2H, d, J = 8.6 Hz), 7.05 (2H, d,J = 8.6 Hz). 20-4

((3S*,4R*)-1-{2- [(tert-butyldimethyl- silyl)oxy]ethyl}-4-(6-fluoro-2,3-dihydro- benzofuran-5-yl)-2- oxopyrrolidin-3-yl) carbamicacid benzyl ester ¹H-NMR (400 MHz, CDCl₃) δ 0.06 (6H, s), 0.88 (9H, s),3.10-3.20 (2H, m), 3.32- 3.39 (1H, m), 3.47-3.61 (3H, m), 3.70-3.79 (3H,m), 4.58-4.64 (3H, m), 5.00- 5.15 (3H, m), 6.51 (1H, d, J = 11.0 Hz),7.10-7.20 (1H, m), 7.26-7.40 (5H, m).

Reference Example 21-1

[(3S*,4R*)-4-(2-Fluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester

To a solution of((3S*,4R*)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamic acid benzyl ester (219 mg) in tetrahydrofuran (4.2 mL),tetrabutylammonium fluoride (465 μL, 1.0 M tetrahydrofuran solution) wasadded to produce a reaction solution. The reaction solution was stirredat room temperature for 30 minutes. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and a brine successively, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=4:1, ethyl acetate, and ethylacetate:methanol=10:1 in turn), to obtain the title compound as a whitesolid (150 mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.73 (1H, brs), 3.40-3.64 (3H, m), 3.65-3.89(7H, m), 4.53 (1H, t, J=9.2 Hz), 5.00-5.12 (2H, brs), 5.25 (1H, brs),6.57-6.73 (2H, m), 7.23-7.35 (6H, m).

The same method as in Reference Example 21-1 was performed using acorresponding [(tert-butyldimethylsilyl)oxy]ethyl substance to obtainthe following Reference Examples 21-2 to 21-4. The structures andspectral data thereof are shown in Table 41.

TABLE 41 Ref. No Str. Chemical name P.D. 21-2

[(3S*,4R*)-4-(2,6-di- fluoro-4-methoxy- phenyl)-1-(2-hydroxy-ethyl)-2-oxopyrrolidin- 3-yl]carbamic acid benzyl ester ¹H-NMR (400 MHz,CDCl₃) δ 2.70 (1H, brs), 3.40-3.48 (1H, m), 3.59-3.70 (3H, m), 3.78 (3H,s), 3.80-3.94 (3H, m), 4.50-4.61 (1H, m), 5.01-5.09 (2H, m), 5.29 (1H,brs), 6.41-6.52 (2H, m), 7.27-7.36 (5H, m). 21-3

[1-(2-hydroxyethyl}- 4-(4-methoxyphenyl)- 2-oxopyrrolidin-3-yl] carbamicacid tert- butyl ester ¹H-NMR (400 MHz, CDCl₃) δ 1.36 (9H, s), 2.71 (1H,brs), 3.50 (1H, dt, J = 14.0, 4.9 Hz), 3.62-3.68 (2H, m), 3.79-3.92 (7H,m), 4.57 (1H, t, J = 7.3 Hz), 4.64 (1H, d, J = 6.8 Hz), 6.83 (2H, d, J =8.6 Hz), 7.07 (2H, d, J = 8.6 Hz). 21-4

[(3S*,4R*)-4-(6- fluoro-2,3-dihydro- benzofuran-5-yl)-1-(2-hydroxyethyl)-2- oxopyrrolidin-3-yl] carabamic acid benzyl ester¹H-NMR (400 MHz, DMSO-d₆) δ 3.10-3.18 (3H, m), 3.30-3.63 (6H, m), 4.42(1H, t, J = 9.8 Hz), 4.56 (2H, t, J = 8.6 Hz), 4.74 1H, t, J = 4.0 Hz),4.99 (2H, s), 6.65 (1H, d, J = 11.0 Hz), 7.28-7.35 (6H, m), 7.62 (1H, d,J = 9.8 Hz).

Reference Example 22-1

(3R*,4S*)-1-Hydroxy-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid methyl ester

Zinc powder (2.0 g) and an aqueous solution (5 mL) of ammonium chloride(0.9 g) was added to a solution of(+)-(S*)-2-[1-(4-methoxyphenyl)-2-nitroethyl]malonic acid dimethyl ester(1.04 g) in methanol (30 mL) to produce a reaction solution. Thereaction solution was stirred for 1 hour. Ethyl acetate was added to thereaction solution, and the reaction solution was filtered over Celite.The filtrate was washed with a 1 mol/L hydrochloric acid, water, and abrine successively, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate), to obtain the titlecompound as a colorless oil (760 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.57 (1H, d, J=8.5 Hz), 3.68 (1H, t, J=8.1Hz), 3.78 (3H, s), 3.79 (3H, s), 3.95 (1H, q, J=8.1 Hz), 4.03 (1H, t,J=8.5 Hz), 6.88 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz).

Reference Example 22-2

(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-hydroxy-2-oxopyrrolidine-3-carboxylicacid methyl ester

The same method as in Reference Example 22-1 was performed using(−)-(R)-2-[1-(2,6-difluoro-4-methoxyphenyl)-2-nitroethyl]malonic aciddimethyl ester in place of(+)-(S*)-2-[1-(4-methoxyphenyl)-2-nitroethyl]malonic acid dimethyl esterto obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.72-3.82 (8H, m), 3.93 (1H, t, J=8.8 Hz),4.33 (1H, q, J=8.8 Hz), 6.48 (2H, d, J=8.6 Hz).

Reference Example 23-1

(3R*,4S*)-1-Methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid methyl ester

Potassium carbonate (276 mg) and iodomethane (0.12 mL) were added to asolution of(3R*,4S*)-1-hydroxy-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid methyl ester (265 mg) in N,N-dimethylformamide (2 mL), to produce areaction solution. The reaction solution was stirred at room temperaturefor 12 hours. Ethyl acetate was added to the reaction solution, and themixture was washed with water and a brine successively, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (ethyl acetate:hexane=1:1), to obtain the title compoundas a colorless oil (220 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.48 (1H, d, J=9.1 Hz), 3.51 (1H, t, J=8.5Hz), 3.78 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 3.90 (1H, dd, J=8.5, 8.2Hz), 3.98 (1H, t, J=8.2 Hz), 6.89 (2H, d, J=9.1 Hz), 7.16 (2H, d, J=9.1Hz).

Reference Example 23-2

(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-methoxy-2-oxopyrrolidine-3-carboxylicacid methyl ester

The same method as in Reference Example 23-1 was performed using(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-hydroxy-2-oxopyrrolidine-3-carboxylicacid methyl ester in place of(3R*,4S*)-1-hydroxy-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid methyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.62 (3H, s), 3.62-3.91 (10H, m), 6.43-6.50(2H, m).

Reference Example 24-1

(3R*,4S*)-1-Methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid

The same method as in Reference Example 8-1 was performed using(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid methyl ester in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.47 (1H, d, J=9.1 Hz), 3.60 (1H, t, J=8.5Hz), 3.80 (3H, s), 3.88 (3H, s), 3.85-3.93 (1H, m), 3.99 (1H, t, J=8.8Hz), 6.90 (2H, d, J=9.1 Hz), 7.23 (2H, d, J=9.1 Hz).

Reference Example 24-2

(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-methoxy-2-oxopyrrolidine-3-carboxylicacid

The same method as in Reference Example 8-1 was performed using(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methoxy-2-oxopyrrolidine-3-carboxylicacid methyl ester in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acidmethyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ3.68-3.91 (9H, m), 4.18-4.26 (1H, m), 6.46-6.52(2H, m).

Reference Example 25-1

(3S*,4R*)-4-[4-(Benzyloxy)-2,6-difluorophenyl]-2-oxopyrrolidine-3-carboxylicacid methyl ester

Potassium carbonate (268 mg) and benzyl bromide (0.23 mL) were added toa solution of(3S*,4R*)-4-(2,6-difluoro-4-hydroxyphenyl)-2-oxopyrrolidine-3-carboxylicacid methyl ester (500 mg) in N,N-dimethylformamide (4 mL), to produce areaction solution. The reaction solution was stirred at room temperaturefor 25 hours. A saturated aqueous ammonium chloride solution was addedto the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (hexane:ethyl acetate=4:1), to obtainthe title compound as a colorless oil (643 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.50 (1H, t, J=8.5 Hz), 3.66 (1H, t, J=8.5Hz), 3.76-3.80 (1H, m), 3.78 (3H, s), 4.46 (1H, q, J=9.5 Hz), 5.02 (2H,s), 5.89 (1H, brs), 6.54 (2H, d, J=10.3 Hz), 7.36-7.40 (5H, m).

Reference Example 26-1

(3S*,4R*)-4-[4-(Benzyloxy)-2,6-difluorophenyl]-2-oxopyrrolidine-3-carboxylicacid

The same method as in Reference Example 8-1 was performed using(3S*,4R*)-4-[4-(benzyloxy)-2,6-difluorophenyl]-2-oxopyrrolidine-3-carboxylicacid methyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d) δ 3.25 (1H, t, J=9.4 Hz), 3.43 (1H, d, J=10.3Hz), 3.56 (1H, d, J=9.1 Hz), 4.15 (1H, q, J=9.4 Hz), 5.11 (2H, s), 6.85(2H, d, J=10.9 Hz), 7.32-7.44 (5H, m), 8.18 (1H, s), 12.76 (1H, brs).

Reference Example 27-1

1-{(3S*,4R*)-4-[4-(Benzyloxy)-2,6-difluorophenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea

The same method as in Example 1-1 was performed using(3S*,4R*)-4-[4-(benzyloxy)-2,6-difluorophenyl]-2-oxopyrrolidine-3-carboxylicacid in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid toobtain the title compound.

¹H-NMR (400 MHz, DMSO-d) δ 3.27-3.32 (1H, m), 3.44 (1H, t, J=8.9 Hz),3.79 (1H, q, J=9.8 Hz), 4.56 (1H, dd, J=11.0, 8.6 Hz), 5.10 (2H, s),6.46 (1H, d, J=8.6 Hz), 6.82 (2H, d, J=10.4 Hz), 6.99-7.05 (2H, m),7.30-7.44 (7H, m), 8.05 (1H, s), 8.66 (1H, s).

The same method as in Reference Example 27-1 was performed using acorresponding carboxylic acid substance to obtain the followingReference Examples 27-2 to 27-4. The structures and spectral datathereof are shown in Table 42.

TABLE 42 Ref. No Str. Chemical name P.D. 27-2

1-[(3S*,4R*)-4-(4- benzyloxy-2,6- difluorophenyl)- 2-oxopyrrolidin-3-yl]-3-phenylurea ¹H NMR (400 MHz, CDCl₃) δ 3.56-3.61 (2H, m), 4.05-4.11(1H, m), 4.67 (1H, t, J = 8.9 Hz), 4.99 (2H, s), 5.88 (1H, brs), 6.34(1H, brs), 6.51 (2H, d, J = 10.4 Hz), 6.92 (1H, t, J = 7.6 Hz), 7.13(1H, t, J = 7.6 Hz), 7.23 (2H, d, J = 7.6 Hz), 7.30-7.40 (5H, m), 7.46(1H, brs). 27-3

(3,5-difluoro-4- {(3R*,4S*)-4-[3- (4-fluorophenyl)- ureido]-5-oxo-pyrrolidin-3-yl}- phenyl)(methyl)- carbamic acid tert-butyl ester ¹H-NMR(400 MHz, CDCl₃) δ 1.49 (9H, s), 3.25 (3H, s), 3.59-3.71 (2H, m),4.18-4.26 (1H, m), 4.54-4.59 (1H, m), 5.75 (1H, brs), 6.03 (1H, brs),6.80-6.85 (2H, m), 6.92 (2H, d, J = 10.4 Hz), 7.13-7.18 (2H, m), 7.29(1H, brs). 27-4

(−)-1-[(3S*,4R*)-4- (1-benzyl-6-fluoro- indolin-5-yl)-2-oxopyrrolidin-3-yl]- 3-(4-fluorophenyl)- urea ¹H-NMR (400 MHz, DMSO- d₆)δ 2.84 (2H, t, J = 8.5 Hz), 3.13 (1H, t, J = 9.7 Hz), 3.27- 3.29 (2H,m), 3.38 (1H, t, J = 8.5 Hz), 3.56-3.64 (1H, m), 4.25 (2H, s), 4.48 (1H,dd, J = 11.5, 9.1 Hz), 6.36-6.40 (2H, m), 7.03 (2H, t, J = 9.1 Hz), 7.14(1H, d, J = 7.9 Hz), 7.25- 7.37 (7H, m), 7.88 (1H, s), 8.55 (1H, s). MS(ESI⁺) m/z: 463 (MH⁺). [α]_(D) ²² = −155 (c 0.10, EtOH)

Reference Example 28-1

Trifluoromethanesulfonoc acid3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}phenylester

To a solution of1-[(3S*,4R*)-4-(2,6-difluoro-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea(365 mg) in dichloromethane (5 mL), pyridine (0.4 mL) andtrifluoromethanesulfonic anhydride (0.25 mL) were added under an argonatmosphere under ice-cooling to produce a reaction solution. Thereaction solution was stirred at room temperature for 3 hours. Water wasadded to the reaction solution, the mixture was extracted with ethylacetate, and the extract was washed with water and a brine, and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=4:1 followed by ethyl acetate), toobtain the title compound as a brown oil (388 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.36 (1H, t, J=9.5 Hz), 3.52 (1H, t, J=9.2Hz), 3.93 (1H, q, J=9.6 Hz), 4.55 (1H, dd, J=10.4, 7.9 Hz), 6.51 (1H, d,J=7.9 Hz), 6.98-7.04 (2H, m), 7.27-7.33 (2H, m), 7.58 (2H, d, J=8.6 Hz),8.13 (1H, s), 8.74 (1H, s).

MS (ESI⁺) m/z: 498 (MH⁺).

Reference Example 29-1

[(3S*,4R*,Z)-2-(Methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbamicacid benzyl ester

Triethyloxonium hexafluoro phosphate (446 mg) was added to a suspensionof (−)-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidbenzyl ester (500 mg) in dichloromethane (3.7 mL) to produce a reactionsolution. The reaction solution was stirred at room temperature for 20hours. After that, a saturated aqueous sodium hydrogen carbonatesolution was added, and the reaction solution was stirred at roomtemperature for 30 minutes, and extracted with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas removed under reduced pressure to obtain[(3R*,4S*)-5-ethoxy-3-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrol-4-yl]carbamicacid benzyl ester that was an intermediate as a yellow oil.

O-methylhydroxylamine hydrochloride (91 mg) was added to a solution of[(3R*,4S*)-5-ethoxy-3-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrolo-4-yl]carbamicacid benzyl ester (325 mg) in methanol (2 mL) to produce a reactionsolution. The reaction solution was stirred at room temperature for 3.5hours. After that, a saturated aqueous sodium hydrogen carbonatesolution was added to the reaction solution under ice-cooling, and themixture was extracted with ethyl acetate. The organic layer was washedwith a brine, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate:hexane=2:1), to obtainthe title compound as a colorless oil (228 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.15 (1H, t, J=9.1 Hz), 3.22-3.30 (1H, m),3.45 (1H, t, J=8.2 Hz), 3.59 (3H, s), 3.72 (3H, s), 4.60 (1H, t, J=9.7Hz), 4.96 (2H, s), 6.63 (1H, s), 6.86 (2H, d, J=8.5 Hz), 7.20-7.34 (7H,m), 7.59 (1H, d, J=9.1 Hz).

The same method as in Reference Example 29-1 was performed using acorresponding Cbz substance and amine to obtain the following ReferenceExamples 29-2 to 29-7.

The structures and spectral data thereof are shown in Tables 43 to 44.

TABLE 43 Ref. No Str. Chemical name P.D. 29-2

[(3S*,4R*,Z)-4-(2- fluoro-4-methoxy- phenyl)-2-(methoxy-imino)pyrrollidin- 3-yl]carbamic acid benzyl ester ¹H-NMR (400 MHz,CDCl₃) δ 3.35 (1H, t, J = 9.2 Hz), 3.48-3.69 (2H, m), 3.70- 3.81 (6H,m), 4.92-5.11 (5H, m), 6.51-6.72 (2H, m), 7.24-7.34 (6H, m). 29-3

[(3S*,4R*,Z)-4-(2, 6-difluoro-4-meth- oxyphenyl)-2- (methoxyimino)-pyrrolidin-3-yl]- carbamic acid benzyl ester ¹H-NMR (400 MHz, CDCl₃) δ3.52-3.58 (2H, m), 3.60- 3.81 (7H, m), 4.94-5.18 (5H, m), 6.40-6.48 (2H,m), 7.26-7.31 (5H, m). 29-4

{(3S*,4R*,Z)-2-[(2- hydroxyethoxy)- imino]-4-(4- methoxyphenyl)-pyrrolidin-3-yl}- carbamic acid benzyl ester ¹H-NMR (400 MHz, DMSO- d₆)δ 3.16 (1H, t, J = 9.1 Hz), 3.24-3.30 (1H, m), 3.47 (1H, t, J = 8.2 Hz),3.53-3.59 (2H, m), 3.72 (3H, s), 3.80 (2H, t, J = 5.1 Hz), 4.44 (1H, t,J = 5.8 Hz) 4.60 (1H, t, J = 9.7 Hz), 4.96 (2H, s), 6.63 (1H, s), 6.86(2H, d, J = 8.5 Hz), 7.20-7.34 (7H, m), 7.61 (1H, d, J = 9.1 Hz). 29-5

{(3S*,4R*,Z)-4-(2, 6-difluoro-4-meth- oxyphenyl)-2-[(2- hydroxyethoxy)-imino]pyrrolidin-3- yl}carbamic acid benzyl ester ¹H-NMR (400 MHz,CDCl₃) δ 2.87 (1H, brs), 3.50-3.64 (2H, m), 3.65-3.80 (4H, m), 3.83-3.90(2H, m), 4.08 (1H, dd, J = 4.3, 4.3 Hz), 4.80-5.15 (3H, m), 5.13 (1H,dd, J = 9.8, 8.0 Hz) 5.25 (1H, s), 6.40-6.50 (2H, m), 7.26-7.32 (5H, m).

TABLE 44 Ref. No Str. Chemical name P.D. 29-6

[(3R*,4S*)-3-(2,6- difluoro-4-methoxy- phenyl)-5-(methyl-amino)-3,4-dihydro- 2H-pyrrolo-4-yl]- carbamic acid benzyl ester ¹H-NMR(400 MHz, DMSO-d₆) δ 2.66 (3H, d, J = 4.9 Hz), 3.34- 3.43 (1H, m),3.45-3.56 (1H, m), 3.63-3.73 (1H, m), 3.75 (3H, s), 4.86 (1H, t, J = 9.5Hz), 4.92 (1H, d, J = 12.8 Hz), 4.99 (1H, d, J = 12.8 Hz), 5.99-6.06(1H, m), 6.70 (2H, d, J = 10.4 Hz), 7.22-7.36 (5H, m), 7.69 (1H, d, J =9.2 Hz). 29-7

((3S*,4R*,Z)-2- {[(tert-butyldimethyl- silyl)oxy]imino}-4-(4-methoxyphenyl)- pyrrolidin-3-yl) carbamic acid benyl ester ¹H-NMR(400 MHz, DMSO-d₆) δ 0.05 (6H, s), 0.90 (9H, s), 3.18 (1H, t, J = 9.1Hz), 3.22-3.40 (1H, m), 3.49 (1H, t, J = 8.2 Hz), 3.72 (3H, s), 4.55(1H, t, J = 9.7 Hz), 4.91 (1H, d, J = 13.3 Hz), 5.03 (1H, d, J = 13.3Hz), 6.49 (1H, s), 6.86 (2H, d, J = 8.5 Hz), 7.20-7.33 (7H, m), 7.58(1H, d, J = 9.1 Hz).

The same method as in Reference Example 29-1 was performed using acorresponding Cbz substance and amine to obtain the following ReferenceExamples 29-8 to 29-13.

The structures and spectral data thereof are shown in Tables 45 to 46.

TABLE 45 Ref. No Str. Chemical name Spectrum data 29-8

((3S*,4R*,Z)-2-{[(tert-butyl- dimethylsilyl)oxy]imino}-4-(2,6-difluoro-4-methoxy- phenyl)pyrrolidin-3-yl) carbamic acid benzylester ¹H-NMR (400 MHz, CDCl₃) δ 0.15 (6H, s), 0.94 (9H, s), 3.50-3.62(2H, m), 3.65- 3.80 (4H, m), 5.01 (2H, brs), 5.06-5.13 (1H, m), 5.31(1H, s), 6.45 (2H, d, J = 10.4 Hz), 7.25-7.35 (5H, m). 29-9

[(3S*,4R*,Z)-4-(2,6-difluoro- 4-methoxyphenyl)-2-(morpho-linoimino)pyrrolidin-3-yl] carbamic acid benzyl ester ¹H-NMR (400 MHz,CDCl₃) δ 2.66-2.72 (4H, m), 3.52-3.82 (10H, m), 4.90-5.07 (3H, m), 5.27(1H, brs), 5.70 (1H, brs), 6.40-6.50 (2H, m), 7.25- 7.35 (5H, m). 29-10

{(3R*,4S*)-3-(2,6-difluoro- 4-methoxyphenyl)-5-[(1-methyl-1H-pyrazol-3-yl)- amino-3,4-dihydro-2H- pyrrol-4-yl}carbamic acidbenzyl ester ¹H-NMR (400 MHz, CDCl₃) δ 3.50-3.80 (6H, m), 3.82 (3H, s),4.95-5.15 (3H, m), 6.06 (1H, s), 6.42-6.52 (2H, m), 7.21 (1H, s),7.25-7.40 (5H, m), 8.50 (1H, brs). 29-11

[(3R*,4S*)-3-(2,6-difluoro- 4-methoxyphenyl)-5-(phenyl-amino-3,4-dihydro-2H- pyrrol-4-yl]carbamic acid benzyl ester ¹H-NMR (400MHz, CDCl₃) δ 3.50-3.90 (5H, m), 4.18-4.32 (1H, m), 4.90-5.20 (3H, m),6.40-6.50 (2H, m), 7.10-7.40 (10H, m), 7.55 (1H, brs).

TABLE 46 Ref. No Str. Chemical name Spectrum data 29-12

{(3S*,4R*,Z)-4-(6- fluoro-2,3-dihydro- benzofuran-5-yl)-2-[(2-hydroxyethoxy)- imino]pyrrolidin-3- yl}carbamic acid benzyl ester¹H-NMR (400 MHz, CDCl₃) δ 3.00 (1H, brs), 3.10-3.20 (2H, m), 3.32-3.36(1H, m), 3.50-3.65 (2H, m), 3.86 (2H, s), 4.07-4.09 (1H, m), 4.93- 5.11(4H, m), 5.23 (1H, s), 6.50 (1H, d, J = 10.4 Hz), 7.15 (1H, d, J = 6.12Hz), 7.26-7.40 (5H, m) 29-13

3-((Z)-{(3S,4R)-3- [(benzyloxycar- bonyl)amino]-4- (2,6-difluoro-4-methoxyphenyl)- pyrrolidin-2- ylidene}amino)- propanoic acid ethyl ester¹H-NMR (400 MHz, CDCl₃) δ: 1.28 (3H, t, J = 7.3 Hz), 2.64-2.78 (1H, m),3.50- 4.20 (9H, m), 4.02-4.09 (1H, m), 4.65-4.75 (1H, m), 4.95-5.20 (3H,m), 5.75 (1H, brs), 6.42-6.52 (2H, m), 7.27-7.37 (5H, m).

Reference Example 30-1

[(3R*,4S*,Z)-2-(Methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbamicacid benzyl ester

The same method as in Reference Example 29-1 was performed using(+)-[(3R*,4S*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidbenzyl ester in place of(−)-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidbenzyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.15 (1H, t, J=9.1 Hz), 3.22-3.30 (1H, m),3.45 (1H, t, J=8.2 Hz), 3.59 (3H, s), 3.72 (3H, s), 4.60 (1H, t, J=9.7Hz), 4.96 (2H, s), 6.63 (1H, s), 6.86 (2H, d, J=8.5 Hz), 7.20-7.34 (7H,m), 7.59 (1H, d, J=9.1 Hz).

Reference Example 31-1

1-((3S*,4R*,Z)-2-{[(tert-Butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea

The same method as in Example 32-1 was followed using(3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl)carbamicacid benzyl ester in place of[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl)carbamicacid benzyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 0.04 (3H, s), 0.05 (3H, s), 0.89 (9H, s),3.17 (1H, t, J=8.8 Hz), 3.28-3.37 (1H, m), 3.53 (1H, t, J=8.5 Hz), 3.71(3H, s), 4.74 (1H, t, J=9.1 Hz), 6.34 (1H, d, J=9.1 Hz), 6.56 (1H, s),6.86 (2H, d, J=8.5 Hz), 7.00-7.04 (2H, m), 7.27 (2H, d, J=8.5 Hz),7.30-7.34 (2H, m), 8.45 (1H, s).

MS (FD⁺) m/z: 472 (M⁺).

Reference Example 31-2

1-((3S*,4R*,Z)-2-{[(tert-Butyldimethylsilyl)oxy]imino}-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea

The same method as in Example 32-1 was followed using((3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl)oxy]imino}-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-3-yl)carbamic acid benzyl ester in place of[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbamicacid benzyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 0.12 (6H, s), 0.93 (9H, s), 3.57-3.64 (2H, m),3.73-3.82 (1H, m), 3.76 (3H, s), 5.12-5.21 (1H, m), 5.38 (1H, brs), 5.47(1H, s), 6.46 (2H, d, J=10.8 Hz), 6.86-6.93 (2H, m), 7.17-7.22 (2H, m),7.39 (1H, brs).

Reference Example 32-1

3-(2,6-Difluoro-4-methoxyphenyl)-2-[(diphenylmethylene)amino]-4-nitrobutanoicacid ethyl ester

Lithium diisopropylamide (1.1 mL, 1.05 M in tetrahydrofuran/hexane) wasadded to a solution of 2-[(diphenylmethylene)amino]acetic acid ethylester (300 mg) in tetrahydrofuran (2.3 mL) at −78° C. to produce areaction solution. The reaction solution was stirred for 1 hour, asolution of (E)-1,3-difluoro-5-methoxy-2-(2-nitrovinyl)benzene (241 mg)in tetrahydrofuran was added, and the reaction solution was stirred atthe same temperature for 15 minutes. The temperature of the reactionsolution was gradually heated up to room temperature, and the reactionsolution was stirred for 30 minutes. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with a brine, and dried over sodium sulfate. Thesolvent was removed, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1), to obtain the title compoundas a yellow oil (543 mg).

¹H-NMR (400 MHz, CDCl₃) δ1.12 (3H, t, J=7.3 Hz), 3.73 (3H, s), 4.00-4.06(2H, m), 4.43 (1H, d, J=7.8 Hz), 4.73-4.95 (3H, m), 6.36 (2H, d, J=10.4Hz), 7.00-7.05 (2H, m), 7.31-7.38 (6H, m), 7.81-7.85 (2H, m).

Reference Example 32-2

2-[(Diphenylmethylene)amino]-3-(4-methoxyphenyl)-4-nitrobutanoic acidethyl ester

The same method as in Reference Example 32-1 was performed using(E)-1-methoxy-4-(2-nitrovinyl)benzene in place of(E)-1,3-difluoro-5-methoxy-2-(2-nitrovinyl)benzene to obtain the titlecompound.

¹H-NMR (400 MHz, CDCl₃) δ1.19 (3H, t, J=6.7 Hz), 3.76 (3H, s), 3.90-4.36(6H, m), 7.05 (2H, d, J=8.6 Hz), 7.24-7.47 (10H, m), 7.63 (2H, d, J=8.6Hz).

Reference Example 33-1

2-[(tert-Butoxycarbonyl)amino]-3-(2,6-difluoro-4-methoxyphenyl)-4-nitrobutanoicacid ethyl ester

Acetic acid (4.2 mL) and water (0.8 mL) were added to3-(2,6-difluoro-4-methoxyphenyl)-2-[(diphenylmethylene)amino]-4-nitrobutyricacid ethyl ester (530 mg) at room temperature to produce a firstreaction solution. The first reaction solution was stirred at 60° C. for7 hours. The reaction solution was concentrated under reduced pressure,a saturated aqueous sodium hydrogen carbonate solution was added to theresidue until the pH was 8, to produce a second reaction solution. Afterthat, tetrahydrofuran (5.0 mL) was added to the second reactionsolution, di-tert-butyl dicarbonate (290 mg) was then added, and themixture was stirred at room temperature for 16 hours. The secondreaction solution was extracted with ethyl acetate, and the organiclayer was washed with a brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (toluene:ethyl acetate=2:1), to obtain the titlecompound as a white solid (315 mg).

¹H-NMR (400 MHz, CDCl₃) δ 1.08 (3H, brt), 1.46 (9H, s), 3.78 (3H, s),4.00-4.10 (2H, m), 4.22-4.33 (1H, m), 4.71 (1H, brt), 4.88 (2H, d, J=7.9Hz), 5.22 (1H, brd), 6.45 (2H, d, J=10.4 Hz).

Reference Example 33-2

2-[(tert-Butoxycarbonyl)amino]-3-(4-methoxyphenyl)-4-nitrobutanoic acidethyl ester

The same method as in Reference Example 33-1 was performed using2-[(Diphenylmethylene)amino]-3-(4-methoxyphenyl)-4-nitrobutanoic acidethyl ester in place of3-(2,6-difluoro-4-methoxyphenyl)-2-[(diphenylmethylene)amino]-4-nitrobutanoicacid ethyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.08 (3H, brt), 1.46 (9H, s), 3.78 (3H, s),3.82 (1H, q, J=8.6 Hz), 4.02 (2H, d, J=6.7 Hz), 4.55 (1H, t, J=6.7 Hz),4.77 (1H, dd, J=13.4, 9.2 Hz), 4.85 (1H, dd, J=13.4, 5.5 Hz), 5.12 (1H,brs), 6.85 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=8.6 Hz).

Reference Example 34-1

(−)-[4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carb amicacid tert-butyl ester(+)-[4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carb amicacid tert-butyl ester

2-[(tert-Butoxycarbonyl)amino]-3-(2,6-difluoro-4-methoxyphenyl)-4-nitrobutanoicacid ethyl ester was used in place of(R*)-2-[l-(4-methoxyphenyl)-2-nitroethyl]malonic acid dimethyl ester,and (±)-[4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carb amicacid tert-butyl ester was obtained in the same method as in ReferenceExample 7-1. The obtained compound was subjected to optical resolutionby high performance liquid chromatography (hexane:methyl tert-butylether:ethanol=45:25:30, flow rate: 15.0 mL) using a column forseparation of enantiomers (CHIRALPAK ID). An isomer A(−) with aretention time of 13.4 minutes and an isomer B(+) with a retention timeof 22.5 minutes that were the title compounds were each obtained as awhite solid by the optical resolution.

Isomer A(−):

¹H-NMR (400 MHz, CDCl₃) δ 1.26 (9H, s), 3.40 (1H, d, J=10.4 Hz), 3.78(3H, s), 3.85 (1H, d, J=10.4, 8.6 Hz), 4.46 (1H, t, J=6.6 Hz), 4.60 (1H,dd, J=9.8, 6.1 Hz), 4.94 (1H, d, J=5.5 Hz), 5.75 (1H, s) 6.44 (2H, d,J=10.0 Hz).

[α]_(D) ²⁵=−131 (c 0.10, EtOH)

Isomer B(+):

¹H-NMR (400 MHz, CDCl₃) δ 1.26 (9H, s), 3.40 (1H, d, J=10.4 Hz), 3.78(3H, s), 3.85 (1H, d, J=10.4, 8.6 Hz), 4.46 (1H, t, J=6.6 Hz), 4.60 (1H,dd, J=9.8, 6.1 Hz), 4.94 (1H, d, J=5.5 Hz), 5.90 (1H, s) 6.44 (2H, d,J=10.0 Hz).

[α]_(D) ²⁵=+144 (c 0.10, EtOH)

Reference Example 34-2

(−)-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acid tert-butylester (+)-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidtert-butyl ester

2-[(tert-Butoxycarbonyl)amino]-3-(4-methoxyphenyl)-4-nitrobutanoic acidethyl ester was used in place of(R*)-2-[1-(4-methoxyphenyl)-2-nitroethyl]malonic acid dimethyl ester,and (±)-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamic acidtert-butyl ester was obtained in the same method as in Reference Example7-1. The obtained compound was subjected to optical resolution by highperformance liquid chromatography (hexane:methyl tert-butylether:ethanol=45:25:30, flow rate: 15.0 mL) using a column forseparation of enantiomers (CHIRALPAK ID). An isomer A(−) with aretention time of 7.5 minutes and an isomer B(+) with a retention timeof 10.2 minutes that were the title compounds were each obtained as awhite solid by the optical resolution.

Isomer A(−):

¹H-NMR (400 MHz, CDCl₃) δ 1.37 (9H, s), 3.56 (1H, d, J=9.8 Hz), 3.80(3H, s), 3.84 (1H, dd, J=10.4, 6.1 Hz), 3.92 (1H, brs), 4.56 (2H, s),5.75 (1H, s), 6.83 (2H, d, J=8.6 Hz), 7.10 (2H, d, J=8.6 Hz).

[α]_(D) ²²=−88 (c 0.10, EtOH)

Isomer B(+):

¹H-NMR (400 MHz, CDCl₃) δ 1.37 (9H, s), 3.56 (1H, d, J=9.8 Hz), 3.80(3H, s), 3.84 (1H, dd, J=10.4, 6.1 Hz), 3.92 (1H, brs), 4.56 (2H, s),5.75 (1H, s), 6.83 (2H, d, J=8.6 Hz), 7.10 (2H, d, J=8.6 Hz).

[α]_(D) ²²=+98 (c 0.10, EtOH)

Reference Example 35-1

1-[(3S,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrroidin-3-yl]-3-{4-[(trimethylsilyl)ethynyl]phenyl}urea

Trimethylsilylacetylene (115 μL) and triethylamine (115 μL) were addedto a solution of1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-iodophenyl)urea(80 mg), bis(triphenylphosphine)palladium(II) dichloride (11.5 mg), andcopper(I) iodide (15.6 mg) in N,N-dimethylformamide (2 mL) to produce areaction solution. The reaction solution was stirred at 50° C. for 9hours. The reaction solution was concentrated under reduced pressure,and the residue was then purified by silica gel column chromatography(hexane:ethyl acetate=1:1, ethyl acetate, and ethyl acetate:methanol=4:1in turn), to obtain the title compound as a colorless solid (67 mg).

¹H-NMR (400 MHz, CDCl₃) δ 0.22 (9H, s), 3.52-3.63 (2H, m), 3.75 (3H, s),4.09 (1H, q, J=9.2 Hz), 4.65 (1H, dd, J=10.4, 7.4 Hz), 6.08 (1H, brs),6.36-6.45 (3H, m), 7.16 (2H, d, J=8.6 Hz), 7.21 (2H, d, J=8.6 Hz), 7.81(1H, brs).

Reference Example 36-1

2-((3S*,4R*)-3-{[(Benzyloxy)carbonyl]amino}-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-1-yl)aceticacid

A 2 mol/L sodium hydroxide aqueous solution (1.26 mL) was added to asolution of2-((3S*,4R*)-3-{[(benzyloxy)carbonyl]amino}-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-1-yl)aceticacid ethyl ester (521 mg) in methanol (25 mL) to produce a reactionsolution. The reaction solution was stirred at room temperature for 5hours. A 1 mol/L Hydrochloric acid was added to the reaction solution tomake the reaction solution acidic (pH: 1), and the mixture was extractedwith ethyl acetate. The organic layer was washed with a brine, and driedover anhydrous sodium sulfate. The solvent was removed to obtain thetitle compound as a white solid (465 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.50-3.58 (2H, m), 3.72-3.79 (4H, m), 3.87(1H, d, J=17.7 Hz), 4.11 (1H, d, J=17.7 Hz), 4.48 (1H, t, J=10.0 Hz),4.94 (1H, d, J=12.2 Hz), 4.99 (1H, d, J=12.2 Hz), 6.78 (2H, d, J=10.4Hz), 7.25-7.35 (5H, m), 7.74 (1H, d, J=9.2 Hz), 12.9 (1H, s).

Reference Example 37-1

((3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-{2-[2-hydroxypropyl)amino]-2-oxoethyl}-2-oxopyrrolidin-3-yl)carbamic acid benzyl ester

1-Hydroxybenzotriazole (35 mg), 1-amino-2-propanol (20 μL), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (57 mg) were added to asolution of2-((3S*,4R*)-3-{[(benzyloxy)carbonyl]amino}-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-1-yl)aceticacid (100 mg) in dichloromethane (1.0 mL) to produce a reactionsolution. The reaction solution was stirred at room temperature for 4hours. Water was added to the reaction solution, and the mixture wasextracted with dichloromethane. The organic layer was washed with abrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the residue was then purified by silica gelcolumn chromatography (ethyl acetate followed by ethylacetate:methanol=4:1), to obtain the title compound (96 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 1.00 (3H, d, J=6.1 Hz), 2.98-3.05 (2H, m),3.54 (2H, t, J=9.2 Hz), 3.60-3.66 (1H, m), 3.77-3.81 (4H, m), 4.04 (1H,d, J=16.5 Hz), 4.47 (1H, t, J=9.8 Hz), 4.68 (1H, q, J=2.0 Hz), 4.97 (2H,dd, J=17.4, 12.5 Hz), 6.76 (2H, d, J=11.0 Hz), 7.26-7.33 (5H, m), 7.73(1H, d, J=9.2 Hz), 7.94 (1H, t, J=5.5 Hz).

Reference Example 37-2

((3S*,4R*)-1-[2-(2-[(Acetylhydrazinyl)-2-oxoethyl]-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)carbamicacid benzyl ester

The same method as in Reference Example 37-1 was performed usingacetylhydrazine in place of 1-amino-2-propanol as amine to obtain thetitle compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.84 (3H, s), 3.55 (2H, d, J=10.4 Hz), 3.76(4H, s), 3.85 (1H, d, J=16.5 Hz), 4.12 (1H, d, J=16.5 Hz), 4.50 (1H, t,J=9.2 Hz), 4.97 (2H, dd, J=16.5, 12.2 Hz), 6.75 (2H, d, J=11.0 Hz),7.25-7.33 (5H, m), 7.70 (1H, d, J=9.2 Hz), 7.94 (2H, s).

Reference Example 38-1

((3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxo-1-{2-oxo-2-[(2-oxopropyl)amino]ethyl}pyrrolidin-3-yl)carbamicacid benzyl ester

2-Iodoxybenzoic acid (131 mg) was added to a solution of((3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-{2-[(2-hydroxypropyl)amino]-2-oxoethyl}-2-oxopyrrolidin-3-yl)carbamic acid benzyl ester(96 mg) in dimethyl sulfoxide (2.0 mL), to produce a reaction solution.The reaction solution was stirred at room temperature for 18 hours. Asaturated aqueous sodium hydrogen carbonate solution was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a brine successively, and dried overanhydrous sodium sulfate. The solvent was removed to obtain the titlecompound (84 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.02 (3H, s), 3.46-3.54 (2H, m), 3.69 (1H,d, J=9.8 Hz), 3.73 (3H, s), 3.82 (1H, d, J=16.5 Hz), 3.91 (2H, d, J=5.5Hz), 4.07 (1H, d, J=16.5 Hz), 4.45 (1H, t, J=11.0 Hz), 4.92 (2H, dd,J=16.5, 12.2 Hz), 6.72 (2H, d, J=10.4 Hz), 7.22-7.31 (5H, m), 7.67 (1H,d, J=9.2 Hz), 8.23 (1H, t, J=5.5 Hz).

Reference Example 39-1

{(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-[(5-methyloxazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}carbamicacid benzyl ester

Triphenylphosphine (325 mg) and triethylamine (860 μL) were added to asolution of((3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxo-1-{2-oxo-2-[(2-oxopropyl)amino]ethyl}pyrrolidin-3-yl)carbamic acid benzyl ester (76 mg) in carbon tetrachloride (7.8 mL) toproduce are action solution. The reaction solution was stirred at 80° C.for 30 minutes, dichloromethane (2 mL) was added, and the reactionsolution was stirred at 80° C. for 4 hours. A saturated aqueous sodiumhydrogen carbonate solution was added to the reaction solution, and themixture was extracted with dichloromethane. The organic layer was washedwith water and a brine successively, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas then purified by silica gel column chromatography(chloroform:methanol=9:1), to obtain the title compound (15 mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.30 (3H, s), 3.58 (2H, brs), 3.77 (4H, s),4.64 (2H, s), 4.75 (1H, dd, J=10.4, 7.3 Hz), 5.02 (2H, d, J=12.2 Hz),5.22 (1H, brs), 6.45 (2H, d, J=9.8 Hz), 6.67 (1H, s), 7.27-7.35 (5H, m).

Reference Example 39-2

{(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}carbamicacid benzyl ester

Triphenylphosphine (151 mg), triethylamine (160 μL), and1,1,1,2,2,2-hexachloroethane (136 mg) were added to a solution of{(3S*,4R*)-1-[2-(2-acetylhydrazinyl)-2-oxoethyl]-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl}carbamicacid benzyl ester (113 mg) in dichloromethane (11.5 mL) to produce areaction solution. The reaction solution was stirred at room temperaturefor 3 hours. A saturated aqueous sodium hydrogen carbonate solution wasadded to the reaction solution, and the mixture was extracted withdichloromethane. The organic layer was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (hexane:ethyl acetate=4:1 followed byethyl acetate), to obtain the title compound (69 mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.54 (3H, s), 3.61 (2H, d, J=8.6 Hz), 3.77(3H, s), 3.82-3.92 (1H, m), 4.70 (1H, t, J=9.8 Hz), 4.76 (2H, s),5.01-5.10 (2H, m), 5.29 (1H, brs), 6.45 (2H, d, J=9.8 Hz), 7.26-7.35(5H, m).

Reference Example 40-1

4-(Difluoromethoxy)-2,6-difluorobenzaldehyde

A solution (reaction solution) of 2,6-difluoro-4-hydroxybenzaldehyde(1.41 g), potassium carbonate (1.48 g), and sodium chlorodifluoroacetate(2.73 g) in a mixture of N,N-dimethylformamide (15.8 mL) and water (1.84mL) was stirred at 100° C. for 1 hour and a half.

The reaction solution was ice-cooled, water (4.1 mL) and concentratedhydrochloric acid (2.8 mL) were added, and the reaction solution wasstirred at room temperature overnight. A2 mol/L sodium hydroxide aqueoussolution was added to the reaction solution under ice-cooling to adjustthe pH to 10, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a brine, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas then purified by silica gel column chromatography (hexane:ethylacetate=95:5 followed by 3:1), to obtain the title compound as a lightbrown oil (1.61 g).

¹H-NMR (400 MHz, CDCl₃) δ 6.63 (1H, t, J=71.5 Hz), 6.78 (2H, d, J=9.1Hz), 10.26 (1H, s).

Reference Example 41-1

3,5-Difluoro-4-formylphenyl trifluoromethanesulfonate

Pyridine (0.8 mL) and trifluoromethanesulfonic anhydride (1.18 mL) wereadded to a solution of 2,6-difluoro-4-hydroxybenzaldehyde (1.03 g) indichloromethane (30 mL) under an argon atmosphere under ice-cooling toproduce a reaction solution. The reaction solution was stirred at roomtemperature for 3 hours. Water was added to the reaction solution, themixture was extracted with ethyl acetate. The extract was washed withwater and a brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was then purified bysilica gel column chromatography (hexane:ethyl acetate=4:1), to obtainthe title compound as a colorless oil (1.5 g).

¹H-NMR (400 MHz, CDCl₃) δ 6.99-7.04 (2H, m), 10.32 (1H, s).

Reference Example 42-1

N-(3,5-Difluoro-4-formylphenyl)acetamide

Acetamide (225 mg), tris (dibenzylideneacetone)dipalladium(0) (116 mg),xantphos (145 mg), and cesium carbonate (1.24 g) were added to asolution of 3,5-difluoro-4-formylphenyl trifluoromethanesulfonate (737mg) in toluene (15 mL) to produce a reaction solution. The reactionsolution was stirred at 100° C. under an argon atmosphere for 5 hours.The reaction solution was filtered over Celite and washed with ethylacetate. The solvent was removed under reduced pressure, and the residuewas then purified by silica gel column chromatography (hexane:ethylacetate=4:1 followed by ethyl acetate), to obtain the title compound asa pale yellow solid (255 mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.22 (3H, s), 7.24 (2H, d, J=10.4 Hz), 7.44(1H, brs), 10.23 (1H, s).

Reference Example 42-2

(3,5-Difluoro-4-formylphenyl) carbamic acid tert-butyl ester

The same method as in Reference Example 42-1 was performed usingtert-butyl carbamate in place of acetamide as a reagent to obtain thetitle compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.53 (9H, s), 6.77 (1H, brs), 7.07 (2H, d,J=11.0 Hz), 10.20 (1H, s).

Reference Example 43-1

(3,5-Difluoro-4-formylphenyl)(methyl)carbamic acid tert-butyl ester

Iodomethane (110 μL) and sodium hydride (51 mg, 60% in oil) were addedto a solution of (3,5-difluoro-4-formylphenyl)carbamic acid tert-butylester (220 mg) in N,N-dimethylformamide (4 mL) under cooling to producea reaction solution. The reaction solution was stirred at roomtemperature for 3 hours. A saturated aqueous ammonium chloride solutionwas added to the reaction solution, and the mixture was extracted withethyl acetate. The organic layer was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate:hexane=4:1), to obtainthe title compound as a colorless oil (150 mg).

¹H-NMR (400 MHz, CDCl₃) δ 1.53 (9H, s), 3.32 (3H, s), 7.05 (2H, d,J=11.0 Hz), 10.25 (1H, s).

Reference Example 44-1

5-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-ol

Sodium borohydride (56 mg) was added to a solution of5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (310 mg) in a mixture oftetrahydrofuran (7 mL) and ethanol (7 mL) under an argon atmosphereunder ice-cooling to produce a reaction solution. The reaction solutionwas stirred at room temperature for 1 hour. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and a brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=4:1), to obtain the title compoundas a colorless solid (290 mg).

¹H-NMR (400 MHz, CDCl₃) δ 1.78 (1H, d, J=7.3 Hz), 1.92-2.01 (1H, m),2.50-2.58 (1H, m), 2.74-2.82 (1H, m), 2.96-3.03 (1H, m), 5.19 (1H, q,J=6.7 Hz), 7.15 (1H, d, J=7.9 Hz), 7.41 (1H, d, J=6.7 Hz).

Reference Example 45-1

[(5-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane

Triethylamine (0.34 mL), N,N-dimethyl-4-aminopyridine (7.4 mg), andtert-butyl dimethyl chlorosilane (274 mg) were added to a solution of5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-ol (280 mg) inN,N-dimethylformamide (2.4 mL) under an argon atmosphere, to produce areaction solution. The reaction solution was stirred at room temperaturefor 3 hours. Water was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and a brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was then purified bysilica gel column chromatography (hexane:ethyl acetate=9:1), to obtainthe title compound as a colorless solid (410 mg).

¹H-NMR (400 MHz, CDCl₃) δ 0.14 (3H, s), 0.17 (3H, s), 0.94 (9H, s),1.89-1.98 (1H, m), 2.40-2.48 (1H, m), 2.68-2.76 (1H, m), 2.88-2.94 (1H,m), 5.16 (1H, t, J=7.0 Hz), 7.01 (1H, d, J=7.9 Hz), 7.36 (1H, d, J=6.1Hz).

Reference Example 46-1

1-[(tert-Butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-indene-5-carbaldehyde

n-Butyllithium (4.15 mL, 2.65 mol/L hexane solution) was slowly added toa solution of[(5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (3.45 g) in tetrahydrofuran (50 mL) at −78° C. under an argonatmosphere to produce a reaction solution. The reaction solution wasstirred for 40 minutes. After that, N,N-dimethylformamide (1.26 mL) wasadded to the reaction solution, and the reaction solution was stirred at−78° C. for 1 hour. A saturated aqueous sodium chloride solution wasadded to the reaction solution, and the mixture was stirred at 0° C. for1 hour and extracted with ethyl acetate. The organic layer was washedwith water and a brine, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was thenpurified by silica gel column chromatography (hexane:ethyl acetate=4:1),to obtain the title compound as a yellow oil (2.63 g).

¹H-NMR (400 MHz, CDCl₃) δ 0.16 (3H, s), 0.19 (3H, s), 0.95 (9H, s),1.91-2.01 (1H, m), 2.44-2.52 (1H, m), 2.71-2.79 (1H, m), 2.96 (1H, dd,J=14.7, 7.9 Hz), 5.22 (1H, t, J=7.6 Hz), 7.05 (1H, d, J=10.4 Hz), 7.67(1H, d, J=6.7 Hz), 10.32 (1H, s).

Reference Example 47-1

2-(2-Bromo-3,5-difluorophenoxy)ethanol

Ethylene glycol (2.65 mL) and N-methyl-2-pyrrolidone (2 mL) were addedto 2-bromo-1,3,5-trifluorobenzene (2.0 g) under an argon atmosphere, andpotassium tert-butoxide (1.28 g) was added under ice-cooling to producea reaction solution. The reaction solution was stirred under heating at90° C. for 2 hours. The reaction solution was cooled to roomtemperature, water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with water and a brine, and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=9:1 followed by 1:1), to obtain thetitle compound as a colorless oil (1.43 g).

¹H-NMR (400 MHz, CDCl₃) δ 2.10 (1H, t, J=6.4 Hz), 4.00-4.04 (2H, m),4.13 (2H, t, J=4.6 Hz), 6.48-6.52 (1H, m), 6.55-6.61 (1H, m).

Reference Example 48-1

2-Bromo-1-(2-bromoethoxy)-3,5-difluorobenzene

Carbon tetrabromide (606 mg) and triphenyl phosphine (575 mg) were addedto a solution of 2-(2-bromo-3,5-difluorophenoxy) ethanol (370 mg) indichloromethane (3.7 mL) under an argon atmosphere under ice-cooling toproduce a reaction solution. The reaction solution was stirred at roomtemperature for 3 hours. The reaction solution was concentrated underreduced pressure, ethyl acetate was added, and the precipitated solidwas removed by filtration. The filtrate was concentrated under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane followed by hexane:ethyl acetate=9:1), to obtainthe title compound as a colorless solid (453 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.69 (2H, t, J=6.4 Hz), 4.32 (2H, t, J=6.4Hz), 6.47 (1H, dt, J=10.0, 2.3 Hz), 6.59 (1H, td, J=8.4, 2.3 Hz).

Reference Example 49-1

4,6-Difluoro-2,3-dihydrobenzofuran

n-Butyllithium (0.55 mL, 2.65 mol/L hexane solution) was added to asolution of 2-bromo-1-(2-bromoethoxy)-3,5-difluorobenzene (440 mg) intetrahydrofuran (5 mL) at −78° C. under an argon atmosphere to produce areaction solution. The reaction solution was stirred for 2 hours, andstirred at room temperature for 1 hour. A saturated aqueous ammoniumchloride solution was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and a brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure to obtain the title compound (205mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.20 (2H, t, J=8.9 Hz), 4.65 (2H, t, J=8.9Hz), 6.28-6.34 (2H, m).

Reference Example 50-1

4,6-Difluoro-2,3-dihydrobenzofuran-5-carbaldehyde

Phosphorus oxychloride (778 μL) was added to a solution of4,6-difluoro-2,3-dihydrobenzofuran (650 mg) in N,N-dimethylformamide(710 μL) under an argon atmosphere, to produce a reaction solution. Thereaction solution was stirred at 100° C. for 20 hours. The reactionsolution was allowed to cool to room temperature, and added to icedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated sodium hydrogen carbonate aqueoussolution and a brine, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was thenpurified by silica gel column chromatography (hexane:ethyl acetate=4:1),to obtain the title compound as a pale yellow oil (121 mg).

¹H-NMR (400 MHz, CDCl₃) δ 3.27 (2H, t, J=8.9 Hz), 4.77 (2H, t, J=8.9Hz), 6.41 (1H, d, J=11.0 Hz), 10.16 (1H, s).

Reference Example 51-1

1-Benzyl-6-fluoroindoline

Potassium carbonate (4.45 g) and benzyl bromide (3.83 mL) were added toa solution of 6-fluoroindoline (4.2 g) in methanol (38 mL), to produce areaction solution. The reaction solution was heated to reflux for 3hours. The reaction solution was allowed to cool to room temperature,and the insoluble was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the residue was then purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1), toobtain the title compound as a pale brown oil (6.14 g).

¹H-NMR (400 MHz, CDCl₃) δ 2.92 (2H, t, J=8.5 Hz), 3.38 (2H, t, J=8.5Hz), 4.23 (2H, s), 6.18 (1H, dd, J=10.9, 2.4 Hz), 6.27-6.32 (1H, m),6.93-6.97 (1H, m), 7.25-7.34 (5H, m).

Reference Example 52-1

1-Benzyl-6-fluoroindoline-5-carbaldehyde

Phosphorus oxychloride (518 μL) was added to a solution of1-benzyl-6-fluoroindoline (1.0 g) in N,N-dimethylformamide (4.9 mL)under ice-cooling, to produce a reaction solution. The reaction solutionwas stirred at 100° C. for 2 hours. The reaction solution was allowed tocool to room temperature, and added to iced water. A 2 mol/L sodiumhydroxide aqueous solution was added to the iced water to adjust the pHto 10, and the mixture was extracted with chloroform. The organic layerwas washed with a brine, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was thenpurified by silica gel column chromatography (hexane:ethyl acetate=8:1followed by 2:1), to obtain the title compound as a pale yellow oil(1.07 g).

¹H-NMR (400 MHz, CDCl₃) δ 3.02 (2H, t, J=8.5 Hz), 3.61 (2H, t, J=8.5Hz), 4.39 (2H, s), 6.05 (1H, d, J=12.1 Hz), 7.25-7.38 (5H, m), 7.48-7.49(1H, m), 10.02 (1H, s).

Example 1-1

(−)-1-(4-Fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea

Triethylamine (131 μL) and diphenylphosphoryl azide (171 μL) were addedto a solution of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid(170 mg) in toluene (3.6 mL) under an argon atmosphere to produce areaction solution. The reaction solution was stirred at room temperaturefor 1 hour. The temperature was heated up to 90° C. and the reactionsolution was stirred for 1 hour. After that, 4-fluoroaniline (140 μL)was added to the reaction solution, and the reaction solution wasstirred at 120° C. for 3 hours. The reaction solution was cooled to roomtemperature, a 1 mol/L hydrochloric acid was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand a brine successively, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was thenpurified by silica gel column chromatography (ethyl acetate:hexane=4:1,ethyl acetate, and ethyl acetate:methanol=10:1 in turn), to obtain thetitle compound as a white solid (44 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.11-3.17 (1H, m), 3.38-3.48 (2H, m), 3.69(3H, s), 4.45 (1H, dd, J=10.9, 9.1 Hz), 6.38 (1H, d, J=9.1 Hz), 6.86(2H, d, J=8.5 Hz), 7.01 (2H, t, J=9.1 Hz), 7.28 (2H, d, J=8.5 Hz),7.32-7.35 (2H, m), 7.88 (1H, s), 8.53 (1H, s).

MS (ESI⁺) m/z: 344 (MH⁺).

[α]_(D) ²⁸=−156 (c 0.10, EtOH)

The same method as in Example 1-1 was performed using a correspondingcarboxylic acid and aromatic amine to obtain the following Examples 1-2to 1-87.

The structures and spectral data thereof are shown in Tables 47 to 75.

TABLE 47 Ex. No Str. Chemical name P.D. 1-2

(−)-1-(4-chlorophenyl)- 3-[(3S*,4R*)-4-(4- methoxyphenyl)-2-oxopyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.11-3.21 (1H, m),3.41- 3.50 (2H, m), 3.71 (3H, s), 4.46 (1H, dd, J = 10.9, 9.1 Hz), 6.47(1H, d, J = 9.1 Hz), 6.87 (2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.1 Hz),7.29 (2H, d, J = 9.1 Hz), 7.38 (2H, d, J = 8.5 Hz), 7.90 (1H, s), 8.67(1H, s). MS (ESI⁺) m/z: 360 (MH⁺). [α]_(D) ²⁸ = −130 (c 0.10, EtOH) 1-3

(−)-1-(3,4-difluoro- phenyl)-3-[(3S*,4R*)- 4-(4-methoxyphenyl)-2-oxopyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.13-3.20 (1H,m), 3.42-3.51 (2H, m), 3.71 (3H, s), 4.45 (1H, t, J = 9.7 Hz), 6.52 (1H,d, J = 8.5 Hz), 6.87 (2H, d, J = 8.5 Hz), 6.98-7.03 (1H, m), 7.21- 7.28(1H, m), 7.29 (2H, d, J = 8.5 Hz), 7.53-7.60 (1H, m), 7.91 (1H, s), 8.76(1H, s). MS (ESI⁺) m/z: 362 (MH⁺). [α]_(D) ²⁸ = −149 (c 0.10, EtOH) 1-4

(−)-1-(2,4-difluoro- phenyl)-3-[(3S*,4R*)- 4-(4-methoxyphenyl)-2-oxopyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.17 (1H, t, J =9.1 Hz), 3.36-3.49 (2H, m), 3.71 (3H, s), 4.47 (1H, dd, J = 11.2, 8.8Hz), 6.80 (1H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 6.93- 6.98 (1H,m), 7.19-7.25 (1H, m), 7.30 (2H, d, J = 8.5 Hz), 7.93 (1H, s), 7.94-8.01(1H, m), 8.28 (1H, s). MS (ESI⁺) m/z: 362 (MH⁺). [α]_(D) ²⁸ = −126 (c0.10, EtOH)

TABLE 48 Ex. No Str. Chemical name P.D. 1-5

(−)-1-(4-cyanophenyl)- 3-[(3S*,4R*)-4-(4- methoxyphenyl)-2-oxopyrrolidin-3-yl] urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.14-3.21 (1H, m),3.43- 3.52 (2H, m), 3.71 (3H, s), 4.48 (1H, t, J = 9.7 Hz), 6.67 (1H, d,J = 9.1 Hz), 6.87 (2H, d, J = 9.1 Hz), 7.29 (2H, d, J = 9.1 Hz), 7.53(2H, dd, J = 7.0, 2.1 Hz), 7.64 (2H, dd, J = 7.0, 2.1 Hz), 7.93 (1H, s),9.09 (1H, s). MS (ESI⁺) m/z: 351 (MH⁺). [α]_(D) ²⁸ = −166 (c 0.10, EtOH)1-6

(−)-1-(4-chlorophenyl)- 3-[(3S*,4R*)-4-(4- methoxyphenyl)-1-methyl-2-oxopyrroli- din-3-yl]urea ¹H-NMR (400 MHz, DMSO- d₆) δ 2.79(3H, s), 3.29 (1H, t, J = 9.7 Hz), 3.43 (1H, q, J = 9.5 Hz), 3.54 (1H,t, J = 8.5 Hz), 3.71 (3H, s), 4.46 (1H, t, J = 10.0 Hz), 6.53 (1H, d, J= 9.1 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.1 Hz), 7.29 (2H,d, J = 9.1 Hz), 7.38 (2H, d, J = 8.5 Hz), 8.71 (1H, s). MS (ESI⁺) m/z:375 (MH⁺). [α]_(D) ²⁶ = −170 (c 0.10, EtOH) 1-7

1-(4-fluorophenyl)- 3-[(3S*,4R*)-4-(4- methoxyphenyl)-1-methyl-2-oxopyrroli- din-3-yl]urea ¹H-NMR (400 MHz, DMSO- d₆) δ 2.79(3H, s), 3.28 (1H, t, J = 10.0 Hz), 3.43 (1H, q, J = 9.5 Hz), 3.54 (1H,t, J = 8.8 Hz), 3.71 (3H, s), 4.47 (1H, t, J = 10.0 Hz), 6.46 (1H, d, J= 9.1 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.02 (2H. t. J = 8.8 Hz), 7.29 (2H,d, J = 8.5 Hz), 7.35 (2H, dd, J = 8.8, 4.8 Hz), 8.58 (1H, s). MS (ESI⁺)m/z: 358 (MH⁺).

TABLE 49 Ex. No Str. Chemical name P.D. 1-8

(−)-1-[(3S*,4R*)-4-(3- fluoro-4-methoxy- phenyl)-2-oxopyrroli-din-3-yl]-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO- d₆) δ3.13-3.20 (1H, m), 3.43-3.50 (2H, m), 3.79 (3H, s), 4.47 (1H, t, J = 9.7Hz), 6.42 (1H, d, J = 8.5 Hz), 7.00-7.14 (4H, m), 7.29-7.37 (3H, m),7.91 (1H, s), 8.58 (1H, s). MS (ESI⁺) m/z: 362 (MH⁺). [α]_(D) ²⁸ = −130(c 0.10, EtOH) 1-9

(−)-1-[(3S*,4R*)-4- (2-fluoro-4-methoxy- phenyl)-2-oxopyrroli-din-3-yl]-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.17(1H, t, J = 9.8 Hz), 3.45 (1H, t, J = 8.9 Hz), 368 (1H, q, J = 9.8 Hz),3.73 (3H, s), 4.56 (1H, dd, J = 11.3, 8.9 Hz), 6.41 (1H, d, J = 8.6 Hz),6.74-6.80 (2H, m), 7.00-7.05 (2H, m), 7.32- 7.37 (2H, m), 7.45 (1H, t, J= 8.9 Hz), 7.94 (1H, s), 8.59 (1H, s). MS (ESI⁺) m/z: 362 (MH⁺). [α]_(D)²⁸ = −99 (c 0.10, EtOH) 1-10

1-[(3S*,4R*)-4-(2- chloro-4-methoxy- phenyl)-2-oxo- pyrrolidin-3-yl]-3-(4-fluorophenyl)urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.07 (1H, t, J = 9.8Hz), 3.50 (1H, t, J = 8.5 Hz), 3.74 3H, s), 3.91 (1H, q, J = 9.8 Hz),4.66 (1H, dd, J = 11.3, 8.9 Hz), 6.42 (1H, d, J = 8.6 Hz), 6.93 (1H, dd,J = 8.6, 2.4 Hz), 7.00-7.06 (3H, m), 7.33-7.37 (2H, m), 7.59 (1H, d, J =8.6 Hz), 7.94 (1H, s), 8.57 (1H, s). MS (ESI⁺) m/z: 378 (MH⁺).

TABLE 50 Ex. No Str. Chemical name P.D. 1-11

(−)-1-(4-fluorophenyl)- 3-[(3S*,4R*)-4-(4- methoxy-2-methyl-phenyl)-2-oxo- pyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO- d₆) δ 2.27(3H, s), 3.05 (1H, t, J = 9.7 Hz), 3.46 (1H, t, J = 8.4 Hz), 3.69 (3H,s), 3.74 (1H, dd, J = 9.8, 8.4 Hz), 4.51 (1H, dd, J = 11.5, 9.1 Hz),6.37 (1H, d, J = 9.1 Hz), 6.71 (1H, d, J = 3.0 Hz), 6.75 (1H, dd, J =8.5, 3.0 Hz), 7.00-7.04 (2H, m), 7.32-7.36 (2H, m), 7.40 (1H, d, J = 8.5Hz), 7.89 (1H, s), 8.51 (1H, s). MS (ESI⁺) m/z: 358 (MH⁺). [α]_(D) ²³ =−187 (c 0.35, EtOH) 1-12

(−)-1-[(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)-2- oxopyrrolidin-3-yl]-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.27-3.33 (1H,m), 3.44 (1H, t, J = 9.5 Hz), 3.75 (3H, s), 3.79 (1H, q, J = 9.8 Hz),4.56 (1H, dd, J = 11.0, 8.6 Hz), 6.46 (1H, d, J = 8.6 Hz), 6.73 (2H, d,J = 10.4 Hz), 6.98-7.04 (2H, m), 7.30-7.34 (2H, m), 8.05 (1H, s), 8.66(1H, s). MS (ESI⁺) m/z: 380 (MH⁺). [α]_(D) ²⁸ = −156 (c 0.10, EtOH) 1-13

(−)-1-[(3S*,4R*)-4- (2,5-difluoro-4- methoxyphenyl)-2-oxopyrrolidin-3-yl]- 3-(4-fluorophenyl)- urea ¹H-NMR (400 MHz, DMSO- d₆)δ 3.18 (1H, t, J = 9.8 Hz), 3.43 (1H, t, J = 8.9 Hz), 3.72 (1H, q, J =9.8 Hz), 3.80 (3H, s), 4.53 (1H, dd, J = 11.6, 8.6 Hz), 6.42 (1H, d, J =8.6 Hz), 7.00-7.10 (3H, m), 7.32-7.36 (2H, m), 7.52 (1H, dd, J = 11.6,8.6 Hz), 7.96 (1H, s), 8.62 (1H, s). MS (ESI⁺) m/z: 380 (MH⁺). [α]_(D)²⁸ = −123 (c 0.10, EtOH)

TABLE 51 Ex. No Str. Chemical name P.D. 1-14

(−)-1-[(3S*,4R*)-4-(3,5- difluoro-4-methoxy- phenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)- urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.13-3.19(1H, m), 3.45-3.56 (2H, m), 3.87 (3H, s), 4.49 (1H, dd, J = 11.3, 8.9Hz), 6.44 (1H, d, J = 9.2 Hz), 7.01-7.07 (2H, m), 7.19-7.26 (2H, m),7.33-7.38 (2H, m), 7.95 (1H, s), 8.61 (1H, s). MS (ESI⁺) m/z: 380 (MH⁺).[α]_(D) ²⁸ = −111 (c 0.10, EtOH) 1-15

(−)-1-[(3S*,4R*)-4-(2,3- dihydrobenzofuran-5- yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl) urea ¹H-NMR (400 MHz, DMSO- d₆) δ 3.10-3.18 (3H,m), 3.39-3.47 (2H, m), 4.40- 4.49 (3H, m), 6.40 (1H, d, J = 8.6 Hz),6.68 (1H, d, J = 8.6 Hz), 7.00-7.08 (3H, m), 7.24 (1H, s), 7.33-7.37(2H, m), 7.88 (1H, s), 8.55 (1H, s). MS (ESI⁺) m/z: 356 (MH⁺). [α]_(D)²⁸ = −130 (c 0.10, EtOH) 1-16

(−)-1-[(3S*,4R*)-4-(6- fluoro-2,3-dihydro- benzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3- (4-fluorophenyl)urea ¹H-NMR (400 MHz, DMSO- d₆) δ3.09-3.18 (3H, m), 3.39-3.46 (1H, m), 3.67 (1H, q, J = 10.0 Hz), 4.50-4.57 (3H, m), 6.41 (1H, d, J = 9.2 Hz), 6.62 (1H, d, J = 11.0 Hz), 7.02(2H, t, J = 8.9 Hz), 7.33-7.38 (3H, m), 7.93 (1H, s), 8.60 (1H, s). MS(ESI⁺) m/z: 374 (MH⁺). [α]_(D) ²⁸ = −152 (c 0.10, EtOH)

TABLE 52 Ex. No Str. Chemical name P.D. 1-17

(−)-1-[(3S*,4R*)- 4-(7-fluoro- chroman-6-yl)-2- oxopyrrolidin-3-yl]-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 1.84-1.90 (2H,m), 2.60-2.73 (2H, m), 3.16 (1H, t, J = 9.8 Hz), 3.42 (1H, t, J = 8.9Hz), 3.64 (1H, q, J = 9.8 Hz), 4.09 (2H, t, J = 4.9 Hz), 4.51 (1H, dd, J= 11.3, 8.9 Hz) 6.40 (1H, d, J = 8.6 Hz), 6.54 (1H, d, J = 11.6 Hz),7.00-7.06 (2H, m), 7.20 (1H, d, J = 8.6 Hz), 7.33-7.37 (2H, m), 7.92(1H, s), 8.58 (1H, s). MS (ESI⁺) m/z: 388 (MH⁺). [α]_(D) ²⁸ = −220 (c0.10, EtOH) 1-18

(−)-1-[(3S*,4R*)- 4-(3-fluoro-5- methoxypyridin- 2-yl)-2-oxo-pyrrolidin-3-yl]- 3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.38 (1H, t, J = 9.2 Hz), 3.47 (1H, t, J = 8.9 Hz), 3.83 (3H, s), 3. 96(1H, q, J = 9.5 Hz), 4.51 (1H, dd, J = 10.4, 7.9 Hz), 6.48 (1H, d, J =7.9 Hz), 7.01 (2H, t, J = 8.9 Hz), 7.29-7.35 (2H, m), 7.38 (1H, dd, J =11.6, 2.4 Hz), 7.95 (1H, s), 8.20 (1H, d, J = 2.4 Hz), 8.62 (1H, s). MS(ESI⁺) m/z: 363 (MH⁺). [α]_(D) ²⁸ = −142 (c 0.10, EtOH) 1-19

(−)-1-(4-fluoro- phenyl)-3- [(3S*,4R*)-4-(5- methoxythiophen-2-yl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.18 (1H,t, J = 9.7 Hz), 3.49 (1H, t, J = 9.5 Hz), 3.60 (1H, q, J = 9.5 Hz), 3.78(3H, s), 4.28 (1H, dd, J = 10.9, 9.1 Hz), 6.11 (1H, d, J = 3.6 Hz), 6.47(1H, d, J = 9.1 Hz), 6.62 (1H, d, J = 3.6 Hz), 7.01-7.08 (2H, m),7.36-7.41 (2H, m), 7.93 (1H, s), 8.64 (1H, s). MS (ESI⁺) m/z: 350 (MH⁺).[α]_(D) ²⁸ = −129 (c 0.10, EtOH)

TABLE 53 Ex. No Str. Chemical name P.D. 1-20

(−)-1-(4-fluoro- phenyl)-3- [(3S*,4R*)-4-(4- methylthio- phenyl)-2-oxo-pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.49 (3H, s),3.20-3.27 (1H, m), 3.50-3.58 (2H, m), 4.54 (1H, t, J = 9.7 Hz), 6.47(1H, d, J = 9.1 Hz), 7.05-7.11 (2H, m), 7.26 (2H, d, J = 8.5 Hz),7.35-7.42 (4H, m), 7.97 (1H, s), 8.61 (1H, s). MS (ESI⁺) m/z: 360 (MH⁺).[α]_(D) ²⁷ = −544 (c 0.26, DMSO) 1-21

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]-3-(4-methyl- sulfonyl- phenyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.10 (3H, s), 3.29-3.31 (1H, m), 3.46 (1H, t, J = 9.2 Hz),3.75 (3H, s), 3.79-3.87 (1H, m), 4.58 (1H, dd, J = 11.0, 8.0 Hz),6.70-6.78 (3H, m), 7.57 (2H, d, J = 9.2 Hz), 7.72 (2H, d, J = 9.2 Hz),8.09 (1H, s), 9.25 (1H, s). MS (ESI⁺) m/z: 440 (MH⁺). [α]_(D) ²⁷ = −138(c 0.10, EtOH) 1-22

(−)-1-(4-chloro- phenyl)-3- [(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.27-3.31 (1H, m), 3.44 (1H, t, J = 9.8 Hz), 3.75 (3H, s), 3.75-3.83(1H, m), 4.56 (1H, t, J = 9.6 Hz), 6.51 (1H, d, J = 8.0 Hz), 6.73 (2H,d, J = 12.0 Hz), 7.22 (2H, d, J = 9.2 Hz), 7.35 (2H, d, J = 9.2 Hz),8.06 (1H, s), 8.79 (1H, s). MS (ESI⁺) m/z: 396 (MH⁺). [α]_(D) ²⁷ = −195(c 0.10, EtOH)

TABLE 54 Ex. No Str. Chemical name P.D. 1-23

(−)-1-(4-cyano- phenyl)-3- [(3S*,4R*)-4- (2,6-difluoro- 4-methoxy-phenyl)-2- oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.26-3.33 (1H, m), 3.45 (1H, t, J = 9.8 Hz), 3.75 (3H, s). 3.78-3.86(1H, m), 4.58 (1H, dd, J = 11.0, 8.0 Hz), 6.70-6.77 (3H, m), 7.51 (2H,d, J = 9.2 Hz), 7.63 (2H, d, J = 9.2 Hz), 8.09 (1H, s), 9.24 (1H, s). MS(ESI⁺) m/z: 387 (MH⁺). [α]_(D) ²⁶ = −163 (c 0.10, EtOH) 1-24

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(4-methoxy- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.29 (1H, t, J = 8.6 Hz), 3.43 (1H, t, J = 8.9 Hz), 3.66 (s, 3H),3.70-3.82 (1H, m), 3.75 (3H, s), 4.55 (1H, dd, J = 10.4, 8.6 Hz), 6.34(1H, d, J = 8.6 Hz), 6.71-6.79 (4H, m), 7.22 (2H, d, J = 8.6 Hz), 8.03(1H, s), 8.40 (1H, s). MS (ESI⁺) m/z: 392 (MH⁺). [α]_(D) ²⁸ = −168 (c0.29, EtOH) 1-25

(−)-1-(benzo[d] [1,3]dioxol-5-yl)- 3-[(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.29 (1H, t, J = 8.6 Hz), 3.43 (1H, t, J = 8.9 Hz), 3.72- 3.82 (1H, m),3.75 (3H, s), 4.55 (1H, dd, J = 11.0, 8.6 Hz), 5.90 (2H, s), 6.37 (1H,d, J = 7.9 Hz), 6.64 (1H, dd, J = 8.3, 2.1 Hz), 6.70-6.76 (3H, m), 7.06(1H, d, J = 2.1 Hz), 8.04 (1H, s), 8.50 (1H, s). MS (ESI⁺) m/z: 406(MH⁺). [α]_(D) ²⁸ = −150 (c 0.30, EtOH)

TABLE 55 Ex. No Str. Chemical name P.D. 1-26

(−)-1-(5-chloro- thiazol-2-yl)- 3-[(3S*,4R*)- 4-(2,6-difluoro-4-methoxy- phenyl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.28-3.31 (1H, m), 3.46 (1H, t, J = 9.8 Hz), 3.75 (3H, s),3.82-3.91 (1H, m), 4.55 (1H, dd, J = 9.8, 6.8 Hz), 6.75 (2H, d, J = 11.0Hz), 6.88 (1H, d, J = 6.8 Hz), 7.31 (1H, s), 8.11 (1H, s), 10.9 (1H, s).MS (ESI⁺) m/z: 403 (MH⁺). [α]_(D) ²⁷ = −88 (c 0.10, EtOH) 1-27

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(pyrimidin- 4-yl)urea 1H-NMR (400 MHz, DMSO-d₆) δ3.27-3.31 (1H, m), 3.46 (1H, t, J = 8.6 Hz), 3.75 (3H, s), 3.80-3.88(1H, m), 4.60 (1H, dd, J = 10.4, 8.0 Hz), 6.75 (2H, d, J = 11.0 Hz),7.46 (1H, d, J = 6.1 Hz), 7.86 (1H, brs), 8.14 (1H, s), 8.44 (1H, d, J =5.5 Hz), 8.70 (1H, s), 9.68 (1H, brs). MS (ESI⁺) m/z: 364 (MH⁺). [α]_(D)²⁹ = −180 (c 0.10, DMSO) 1-28

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(pyridin-2- yl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.27-3.30 (1H, m), 3.40- 3.47 (1H, m), 3.75 (3H, s), 3.79-3.88 (1H, m),4.58-4.63 (1H, m), 6.73 (2H, d, J = 10.4 Hz), 6.90-6.93 (1H, m), 7.28(1H, d, J = 8.0 Hz), 7.62-7.67 (1H, m), 8.10 (1H, m), 8.14-8.16 (1H, m),8.37-8.43 (1H, m), 9.22 (1H, s). MS (ESI⁺) m/z: 363 (MH⁺). [α]_(D) ²⁷ =−188 (c 0.10, EtOH)

TABLE 56 Ex. No Str. Chemical name P.D. 1-29

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]-3-(pyridin- 3-yl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.28-3.31 (1H, m), 3.45 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.82 (1H, q,J = 9.5 Hz), 4.57 (1H, dd, J = 11.0, 8.6 Hz), 6.66 (1H, d, J = 8.6 Hz),6.74 (2H, d, J = 10.4 Hz), 7.21 (1H, dd, J = 8.6, 4.9 Hz), 7.78-7.82(1H, m), 8.07 (1H, s), 8.08-8.10 (1H, m), 8.47 (1H, d, J = 2.4 Hz), 8.87(1H, s). MS (ESI⁺) m/z: 363 (MH⁺). [α]_(D) ²⁷ = −168 (c 0.10, EtOH) 1-30

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]-3-(pyrimidin- 5-yl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.28-3.50 (2H, m), 3.74 (3H, s), 3.75-3.90 (1H, m), 4.58 (1H, dd, J =9.8, 8.6 Hz), 6.74 (2H, d, J = 10.4 Hz), 6.92 (1H, d, J = 8.6 Hz), 8.08(1H, s), 8.71 (1H, s), 8.78 (2H, s), 9.11 (1H, s). MS (ESI⁺) m/z: 364(MH⁺). [α]_(D) ²⁸ = −139 (c 0.10, DMSO) 1-31

(−)-1-(6-chloro- pyridin-3-yl)- 3-[(3S*,4R*)- 4-(2,6-difluoro-4-methoxy- phenyl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.28-3.31 (1H, m) , 3.45 (1H, t, J = 9.2 Hz), 3.75 (3H, s),3.83 (1H, q, J = 9.2 Hz), 4.57 (1H, dd, J = 11.0, 8.6 Hz), 6.70-6.79(3H, m), 7.32 (1H, d, J = 8.6 Hz), 7.86 (1H, dd, J = 8.6, 3.0 Hz), 8.07(1H, s), 8.34 (1H, d, J = 3.0 Hz), 9.07 (1H, s). MS (ESI⁺) m/z: 397(MH⁺). [α]_(D) ²⁷ = −152 (c 0.10, EtOH)

TABLE 57 Ex. No Str. Chemical name P.D. 1-32

(−)-1-(5-chloro- pyridin-2-yl)- 3-[(3S*,4R*)- 4-(2,6-difluoro-4-methoxy- phenyl)-2-oxo- pyrrolidin-3- yl]urea 1H-NMR (400 MHz,DMSO-d₆) δ 3.29-3.35 (1H, m), 3.47 (1H, t, J = 9.2 Hz), 3.75 (3H, s),3.81 (1H, q, J = 9.2 Hz), 4.59 (1H, dd, J = 11.0, 8.6 Hz), 6.74 (2H, d,J = 11.0 Hz), 7.49 (1H, d, J = 8.6 Hz), 7.73-7.79 (2H, m), 8.11 (1H, s),8.20 (1H, d, J = 3.0 Hz), 9.35 (1H, s). MS (ESI⁺) m/z: 397 (MH⁺).[α]_(D) ²⁷ = −180 (c 0.10, EtOH) 1-33

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]-3-(pyrazin- 2-yl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.36-3.30 (1H, m), 3.48 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.85 (1H, q,J = 9.5 Hz), 4.60 (1H, dd, J = 10.4, 8.6 Hz), 6.74 (2H, d, J = 11.0 Hz),7.70 (1H, d, J = 8.6 Hz), 8.12 (1H, s), 8.16-8.22 (2H, m), 8.79 (1H, s),9.51 (1H, s). MS (ESI⁺) m/z: 364 (MH⁺). [α]_(D) ²⁸ = −178 (c 0.10, DMSO)1-34

(−)-1-(benzo[d] thiazol-2-yl)- 3-[(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.29-3.36 (1H, m), 3.48 (1H, t, J = 8.6 Hz), 3.75 (3H, s), 3.89 (1H, q,J = 9.2, Hz), 4.60 (1H, dd, J = 10.4, 9.2 Hz), 6.75 (2H, d, J = 11.0Hz), 7.06-7.23 (2H, m), 7.30-7.37 (1H, m), 7.54-7. 62 (1H, m), 7.83 (1H,d, J = 6.7 Hz), 8.14 (1H, s), 11.0 (1H, brs). MS (ESI⁺) m/z: 419 (MH⁺).[α]_(D) ²⁸ = −164 (c 0.10, DMSO)

TABLE 58 Ex. No Str. Chemical name P.D. 1-35

(−)-1-(benzo[b] thiophen-2-yl)- 3-[(3S*,4R*)-4- (2,6-difluoro-4-methoxy- phenyl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.27-3.31 (1H, m), 3.46 (1H, t, J = 8.6 Hz), 3.75 (3H, s),3.86 (1H, q, J = 9.2 Hz), 4.59 (1H, dd, J = 11.0, 8.6 Hz), 6.66 (1H, s),6.75 (2H, d, J = 11.0 Hz), 6.82 (1H, d, J = 8.6 Hz), 7.09 (1H, t, J =8.0 Hz), 7.21 (1H, t, J = 8.0 Hz), 7.52 (1H, d, J = 8.0 Hz), 7.69 (1H,d, J = 8.0 Hz), 8.09 (1H, s), 10.1 (1H, s). MS (ESI⁺) m/z: 418 (MH⁺).[α]_(D) ²⁷ = −74 (c 0.10, EtOH) 1-36

(−)-1-(benzo[d] oxazol-2-yl)- 3-[(3S*,4R*)-4- (2,6-difluoro- 4-methoxy-phenyl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.32-3.38 (1H, m), 3.51 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.97 (1H, q,J = 9.5 Hz), 4.67 (1H, dd, J = 9.8, 8.0 Hz), 6.74 (2H, d, J = 11.0 Hz),7.17-7.30 (2H, m), 7.46-7.57 (2H, m), 8.16 (1H, s), 8.57 (1H, d, J = 7.3Hz), 11.14 (1H, brs). MS (ESI⁺) m/z: 403 (MH⁺). [α]_(D) ²⁸ = −158 (c0.10, EtOH) 1-37

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]-3-(5-methyl- isoxazol-3- yl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.29 (3H, s), 3.27-3.32 (1H, m), 3.45 (1H, t, J = 9.2 Hz),3.75 (3H, s), 3.76-3.84 (1H, m), 4.55 (1H, t, J = 9.8 Hz), 6.31 (1H, s),6.70-6.81 (3H, m), 8.09 (1H, s), 9.44 (1H, s). MS (ESI⁺) m/z: 367 (MH⁺).[α]_(D) ²⁷ = −154 (c 0.10, EtOH)

TABLE 59 Ex. No Str. Chemical name P.D. 1-38

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(2-fluoro- phenyl)urea 1H-NMR (400 MHz, DMSO-d₆) δ3.29-3.35 (1H, m), 3.46 (1H, t, J = 9.2 Hz), 3.67-3.74 (1H, m), 3.75(3H, s), 4.57 (1H, dd, J = 11.0, 8.6 Hz), 6.75 (2H, d, J = 10.4 Hz),6.88-6.96 (2H, m), 7.03 (1H, t, J = 7.2 Hz), 7.12-7.18 (1H, m),7.93-7.98 (1H, m), 8.11 (1H, s), 8.41 (1H, d, J = 2.4 Hz). MS (ESI⁺)m/z: 380 (MH⁺). [α]_(D) ²⁷ = −152 (c 0.10, EtOH) 1-39

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(5-methyl- thiophen-2- yl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.25 (3H, s), 3.26-3.32 (1H, m), 3.43 (1H, t, J = 9.2 Hz),3.75 (3H, s), 3.76-3.84 (1H, m), 4.53 (1H, dd, J = 9.2, 8.0 Hz), 6.17(1H, d, J = 3.2 Hz), 6.38 (1H, br s), 6.52 (1H, d, J = 8.0 Hz), 6.73(2H, d, J = 10.3 Hz), 8.03 (1H, s), 9.42 (1H, s). MS (ESI⁺) m/z: 382(MH⁺). [α]_(D) ²⁷ = −162 (c 0.10, EtOH) 1-40

(−)-1-(4-fluoro- phenyl)-3- [(3S*,4R*,5S*)- 4-(4-methoxy-phenyl)-5-methyl- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ0.68 (3H, d, J = 6.7 Hz), 3.64-3.71 (1H, m), 3.71 (3H, s), 3.74-3.80(1H, m), 4.79 (1H, dd, J = 12.1, 9.1 Hz), 6.37 (1H, d, J = 9.1 Hz), 6.89(2H, d, J = 9.1 Hz), 7.01-7.06 (2H, m), 7.25 (2H, d, J = 8.5 Hz),7.35-7.39 (2H, m), 8.05 (1H, s), 8.51 (1H, s). MS (ESI⁺) m/z: 358 (MH⁺).[α]_(D) ²⁵ = −149 (c 0.22, EtOH).

TABLE 60 Ex. No Str. Chemical name P.D. 1-41

(−)-1-(4-fluoro- phenyl)-3- [(3S*,4R*,5R*)- 4-(4-methoxy-phenyl)-5-methyl- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ1.04 (3H, d, J = 6.1 Hz), 2.86 (1H, dd, J = 11.5, 9.1 Hz), 3.45-3.54(1H, m), 3.71 (3H, s), 4.53 (1H, dd, J = 11.5, 8.5 Hz), 6.34 (1H, d, J =8.5 Hz), 6.87 (2H, d, J = 8.5 Hz), 6.99-7.03 (2H, m), 7.27 (2H, d, J =8.5 Hz), 7.31-7.34 (2H, m), 7.98 (1H, s), 8.50 (1H, s). MS (ESI⁺) m/z:358 (MH⁺). [α]_(D) ²⁵ = −108 (c 0.39, EtOH) 1-42

1-[(3S*,4R*)-4- (4-ethyl-2,6- difluorophenyl)- 2-oxopyrrolidin-3-yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 1.15 (3H, t, J= 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.29-3.36 (1H, m), 3.41-3.48 (1H,m), 3.86 (1H, q, J = 9.8 Hz), 4.59 (1H, dd, J = 10.4, 8.6 Hz), 6.48 (1H,d, J = 8.6 Hz), 6.96 (2H, d, J = 9.8 Hz), 7.01 (2H, t, J = 8.9 Hz),7.30-7.34 (2H, m), 8.06 (1H, s), 8.68 (1H, s). MS (ESI⁺) m/z: 378 (MH⁺).1-43

(+)-1-(4-chloro- phenyl)-3- [(3R*,4S*)-2- oxo-4-phenyl- pyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.17-3.23 (1H, m), 3.49-3.58 (2H,m), 4.51 (1H, dd, J = 11.2, 8.5 Hz), 6.51 (1H, d, J = 8.5 Hz), 7.21-7 25(3H, m), 7.29-7.33 (2H, m), 7.36-7.39 (4H, m), 7.94 (1H, s), 8.70 (1H,s). MS (ESI⁺) m/z: 330 (MH⁺). [α]_(D) ²⁵ = +122 (c 0.35, DMSO)

TABLE 61 Ex. No Str. Chemical name P.D. 1-44

(+)-1-(4-chloro- phenyl)-3- [(3R*,4S*)-4- (4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.11-3.21 (1H, m),3.41-3.50 (2H, m), 3.71 (3H, s), 4.46 (1H, dd, J = 10.9, 9.1 Hz), 6.47(1H, d, J = 9.1 Hz), 6.87 (2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.1 Hz),7.29 (2H, d, J = 9.1 Hz), 7.38 (2H, d, J = 8.5 Hz), 7.90 (1H, s), 8.67(1H, s). MS (ESI⁺) m/z: 360 (MH⁺). [α]_(D) ²⁵ = +146 (c 0.30, EtOH) 1-45

(+)-1-(4-chloro- phenyl)-3- [(3R*,4S*)-4- (3-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.16-3.23 (1H, m),3.47-3.56 (2H, m), 3.72 (3H, s), 4.52 (1H, t, J = 9.7 Hz), 6.49 (1H, d,J = 9.1 Hz), 6.80 (1H, dd, J = 8.5, 2.1 Hz), 6.93 (1H, d, J = 7.4 Hz),6.97 (1H, s), 7.20-7.24 (3H, m), 7.38 (2H, d, J = 8.5 Hz), 7.92 (1H, s),8.68 (1H, s). MS (ESI⁺) m/z: 360 (MH⁺). [α]_(D) ²⁵ = +115 (c 0.35, DMSO)1-46

(+)-1-(4-chloro- phenyl)-3- [(3R*,4S*)-4- (2-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.09 (1H, t, J = 9.4Hz), 3.40-3.50 (1H, m), 3.69-3.75 (1H, m), 3.78 (3H, s), 4.72 (1H, dd, J= 11.2, 8.8 Hz), 6.45 (1H, d, J = 9.1 Hz), 6.88-6.93 (1H, m), 6.98 (1H,d, J = 7.3 Hz), 7.20-7.24 (3H, m), 7.34-7.39 (3H, m), 7.88 (1H, s), 8.66(1H, s). MS (ESI⁺) m/z: 360 (MH⁺). [α]_(D) ²⁵ = +110 (c 0.35, EtOH)

TABLE 62 Ex. No Str. Chemical name P.D. 1-47

(+)-1-[(3R*,4S*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.27-3.33 (1H, m), 3.44 (1H, t, J = 9.5 Hz), 3.75 (3H, s), 3.79 (1H, q,J = 9.8 Hz), 4.56 (1H, dd, J = 11.0, 8.6 Hz), 6.46 (1H, d, J = 8.6 Hz),6.73 (2H, d, J = 10.4 Hz), 6.98-7.04 (2H, m), 7.30-7.34 (2H, m), 8.05(1H, s), 8.66 (1H, s). MS (ESI⁺) m/z: 380 (MH⁺). [α]_(D) ²⁸ +175 (c0.10, EtOH) 1-48

(+)-1-(4-chloro- phenyl)-3- [(3R*,4S*)-4- (4-methoxy- phenyl)-1-methyl-2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.79 (3H, s),3.29 (1H, t, J = 9.7 Hz), 3.43 (1H, q, J = 9.5 Hz), 3.54 (1H, t, J = 8.5Hz), 3.71 (3H, s), 4.46 (1H, t, J = 10.0 Hz), 6.53 (1H, d, J = 9.1 Hz),6.88 (2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.1 Hz), 7.29 (2H, d, J = 9.1Hz), 7.38 (2H, d, J = 8.5 Hz), 8.71 (1H, s). MS (ESI⁺) m/z: 374 (MH⁺).[α]_(D) ²⁵ = +162 (c 0.31, EtOH) 1-49

(+)-1-(4-fluoro- phenyl)-3- [(3R*,4S*,5S*)- 4-(4-methoxy-phenyl)-5-methyl- 2-oxopyrrolidin- 3-yl]urea 1H-NMR (400 MHz, DMSO-d₆) δ1.04 (3H, d, J = 6.1 Hz), 2.86 (1H, dd, J = 11.5, 9.1 Hz), 3.45-3.54(1H, m), 3.71 (3H, s), 4.53 (1H, dd, J = 11.5, 8.5 Hz), 6.34 (1H, d, J =8.5 Hz), 6.87 (2H, d, J = 8.5 Hz), 6.99-7.03 (2H, m), 7.27 (2H, d, J =8.5 Hz), 7.31-7.34 (2H, m), 7.98 (1H, s), 8.50 (1H, s). MS (ESI⁺) m/z:358 (MH⁺). [α]_(D) ²⁵ +116 (c 0.38, EtOH).

TABLE 63 Ex. No Str. Chemical name P.D. 1-50

(+)-1-(4-fluoro- phenyl)-3- [(3R*,4S*,5R*)- 4-(4-methoxy-phenyl)-5-methyl- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ0.68 (3H, d, J = 6.7 Hz), 3.64-3.71 (1H, m), 3.71 (3H, s), 3.74-3.80(1H, m), 4.79 (1H, dd, J = 12.1, 9.1 Hz), 6.37 (1H, d, J = 9.1 Hz), 6.89(2H, d, J = 9.1 Hz), 7.01-7.06 (2H, m), 7.25 (2H, d, J = 8.5 Hz),7.35-7.39 (2H, m), 8.05 (1H, s), 8.51 (1H, s). MS (ESI⁺) m/z: 358 (MH⁺).[α]_(D) ²⁵ +167 (c 0.45, EtOH). 1-51

(+)-1-(4-fluoro- phenyl)-3- [(3R*,4S*)-4- (5-methoxy- thiophen-2-yl)-2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.18 (1H, t, J =9.7 Hz), 3.49 (1H, t, J = 9.5 Hz), 3.60 (1H, q, J = 9.5 Hz), 3.78 (3H,s), 4.28 (1H, dd, J = 10.9, 9.1 Hz), 6.11 (1H, d, J = 3.6 Hz), 6.47 (1H,d, J = 9.1 Hz), 6.62 (1H, d, J = 3.6 Hz), 7.04 (2H, m), 7.37-7.40 (2H,m), 7.93 (1H, s), 8.64 (1H, s). MS (ESI⁺) m/z: 350 (MH⁺). [α]_(D) ²⁵ =+122 (c 0.10, EtOH) 1-52

(+)-1-{(3R*,4S*)- 4-[4-(difluoro- methoxy)phenyl]- 2-oxopyrrolidin-3-yl}-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.17-3.22 (1H,m), 3.47-3.57 (2H, m), 4.50 (1H, dd, J = 10.9, 9.1 Hz), 6.44 (1H, d, J =9.1 Hz), 7.00-7.05 (2H, m), 7.00-7.37 (1H, m), 7.12 (2H, d, J = 8.5 Hz),7.33-7.37 (2H, m), 7.44 (2H, d, J = 8.5 Hz), 7.94 (1H, s), 8.57 (1H, s).MS (ESI⁺) m/z: 380 (MH⁺). [α]_(D) ²³ = +107 (c 0.35, EtOH)

TABLE 64 Ex. No Str. Chemical name P.D. 1-53

(±)-trans-1-(4- chlorophenyl)- 3-[4-(4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.11-3.21 (1H, m), 3.41-3.50 (2H,m), 3.71 (3H, s), 4.46 (1H, dd, J = 10.9, 9.1 Hz), 6.47 (1H, d, J = 9.1Hz), 6.87 (2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.1 Hz), 7.29 (2H, d, J= 9.1 Hz), 7.38 (2H, d, J = 8.5 Hz), 7.90 (1H, s), 8.67 (1H, s). MS(ESI⁺) m/z: 360 (MH⁺). 1-54

(±)-trans-1-(4- fluorophenyl)- 3-[4-(4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.11-3.17 (1H, m),3.38-3.48 (2H, m), 3.69 (3H, s), 4.45 (1H, dd, J = 10.9, 9.1 Hz), 6.38(1H, d, J = 9.1 Hz), 6.86 (2H, d, J = 8.5 Hz), 7.01 (2H, t, J = 9.1 Hz),7.28 (2H, d, J = 8.5 Hz), 7.32-7.35 (2H, m), 7.88 (1H, s), 8.53 (1H, s).MS (ESI⁺) m/z: 344 (MH⁺). 1-55

(±)-trans-1-(4- chlorophenyl)- 3-[4-(4-methoxy- phenyl)-1- methyl-2-oxo-pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.79 (3H, s), 3.29(1H, t, J = 9.7 Hz), 3.43 (1H, q, J = 9.5 Hz), 3.54 (1H, t, J = 8.5 Hz),3.71 (3H, s), 4.46 (1H, t, J = 10.0 Hz), 6.53 (1H, d, J = 9.1 Hz), 6.88(2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.1 Hz), 7.29 (2H, d, J = 9.1 Hz),7.38 (2H, d, J = 8.5 Hz), 8.71 (1H, s). MS (ESI⁺) m/z: 374 (MH⁺).

TABLE 65 Ex. No. Str. Chemical name P.D. 1-56

1-[(3S*,4R*)-4- (2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(4-hydroxy- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.26-3.31 (1H, m), 3.43 (1H, t, J = 9.7 Hz), 3.72-3.79 (4H, m), 4.64(1H, dd, J = 10.3, 7.8 Hz), 6.29 (1H, d, J = 8.5 Hz), 6.57-6.60 (2H, m),6.73 (2H, d, J = 10.9 Hz), 7.06-7.09 (2H, m), 8.02 (1H, s), 8.25 (1H,s), 8.92 (1H, s). MS (ESI⁺) m/z: 378 (MH⁺). 1-57

1-[(3S*,4R*)-4- (2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(3-hydroxy- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.27-3.32 (1H, m), 3.44 (1H, t, J = 9.7 Hz), 3.72-3.80 (4H, m), 4.56(1H, dd, J = 10 9, 8.5 Hz), 6.27 (1H, dd, J = 7.3, 1.8 Hz), 6.37 (1H, d,J = 8.5 Hz), 6.65 (1H, dd, J = 7.2, 1.8 Hz), 6.73 (2H, d, J = 10.9 Hz),6.91-6.96 (2H, m), 8.05 (1H, s), 8.49 (1H, s), 9.16 (1H, s). MS (ESI⁺)m/z: 378 (MH⁺). 1-58

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(3-methyl- isothiazol-5- yl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.21 (3H, s), 3.27-3.32 (1H, m), 3.45 (1H, t, J = 9.6 Hz),3.75 (3H, s), 3.87 (1H, q, J = 9.6 Hz), 4.54 (1H, dd, J = 9.6, 8.6 Hz),6.46 (1H, s), 6.75 (2H, d, J = 10.4 Hz), 7.16 (1H, d, J = 8.6 Hz), 8.09(1H, s), 10.5 (1H, s). MS (ESI⁺) m/z: 383 (MH⁺). [α]_(D) ²⁶ = −264 (c0.03, EtOH)

TABLE 66 Ex. No. Str. Chemical name P.D. 1-59

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3- yl]-3-(1H-indol- 5-yl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.30 (1H, t, J = 9.2 Hz), 3.44 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.77(1H, q, J = 9.2 Hz), 4.58 (1H, dd, J = 10.4, 8.6 Hz), 6.27 (1H, brs),6.32 (1H, d, J = 8.6 Hz), 6.71-6.77 (2H, d, J = 10.4 Hz), 6.94 (1H, dd,J = 8.6, 1.8 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.23 (1H, t, J = 3.0 Hz),7.52 (1H, d, J = 1.8 Hz), 8.04 (1H, s), 8.31 (1H, s), 10.9 (1H, s). MS(ESI⁺) m/z: 401 (MH⁺). [α]_(D) ²⁷ = −156 (c 0.11, EtOH) 1-60

1-[(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(4-iodo- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.25-3.34 (1H,m), 3.44 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.79 (1H, q, J = 9.2 Hz),4.55 (1H, dd, J = 11, 8.6 Hz), 6.53-6.65 (1H, m), 6.79-6.77 (2H, m),7.18 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.6 Hz), 8.05 (1H, s),8.79-8.88 (1H, m). MS (ESI⁺) m/z: 488 (MH⁺). 1-61

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-[4-(oxazol-2- yl)phenyl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.26-3.33 (1H, m), 3.46 (1H, t, J = 9.2 Hz), 3.75 (3H, s),3.82 (1H, q, J = 9.2 Hz), 4.58 (1H, dd, J = 10.4, 8.0 Hz), 6.64 (1H,brs), 6.71-6.78 (2H, m), 7.29 (1H, s), 7.49 (2H, d, J = 8.6 Hz), 7.80(2H, d, J = 8.6 Hz), 8.08 (1H, s), 8.11 (1H, s), 9.02 (1H, brs) . MS(ESI⁺) m/z: 429 (MH⁺) . [α]_(D) ²⁹ = −166 (c 0.15, EtOH)

TABLE 67 Ex. No. Str. Chemical name P. D. 1-62

(−)-1-(4-cyclo- propylphenyl)-3- [(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)-2- oxopyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ0.52-0.56 (2H, m), 0.81-0.87 (2H, m), 1.76-1.82 (1H, m), 3.29 (1H, t, J= 9.2 Hz), 3.44 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.77 (1H, q, J = 9.2Hz), 4.55 (1H, dd, J = 10.4, 8.6 Hz), 6.39 (1H, d, J = 8.6 Hz),6.70-6.76 (2H, m), 6.89 (2H, d, J = 8.6 Hz), 7.18 (2H, d, J = 8.6 Hz),8.04 (1H, s), 8.50 (1H, s). MS (ESI⁺) m/z: 402 (MH⁺). [α] _(D) ²⁵ = −157(c 0.14, EtOH) 1-63

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-[4-(trifluoro- methyl)phenyl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.29-3.35 (1H, m), 3.47 (1H, t, J = 9.2 Hz), 3.76 (3H, s) , 3.80-3.88(1H, m), 4.60 (1H, dd, J = 11.0, 8.6 Hz), 6.65 (1H, d, J = 7.9 Hz), 6.75(2H, d, J = 11.0 Hz), 7.50-7.55 (4H, m), 8.09 (1H, s), 9.11 (1H, s). MS(ESI⁺) m/z: 430 (MH⁺). [α] _(D) ²⁶ = −95 (c 0.13, EtOH) 1-64

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(3-fluoro-4- methylphenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.10(3H, s), 3.25-3.35 (1H, m), 3.41-3.47 (1H, m), 3.75 (3H, s), 3.77-3.83(1H, m), 4.55 (1H, dd, J = 11.0, 8.6 Hz), 6.52 (1H, d, J = 8.6 Hz), 6.73(2H, d, J = 11.0 Hz), 6.91 (1H, dd, J = 8.3, 2.1 Hz), 7.06 (1H, t, J =8.9 Hz), 7.28 (1H, dd, J = 12.5, 2.1 Hz), 8.05 (1H, s), 8.77 (1H, s). MS(ESI⁺) m/z: 394 (MH⁺). [α] _(D) ²⁵ = −125 (c 0.13, EtOH)

Ex. No. Str. Chemical name P. D. 1-65

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(4-fluoro-3- methylphenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.14(3H, s), 3.26-3.33 (1H, m), 3.44 (1H, t, J = 8.9 Hz), 3.75 (3H, s),3.77-3.83 (1H, m), 4.55 (1H, dd, J = 11.0, 8.6 Hz), 6.44 (1H, d, J = 8.6Hz), 6.73 (2H, d, J = 11.0 Hz), 6.94 (1H, t, J = 9.2 Hz), 7.07-7.12 (1H,m), 7.23-7.26 (1H, m), 8.04 (1H, s), 8.57 (1H, s). MS (ESI⁺) m/z: 394(MH⁺). [α] _(D) ²⁶ = −151 (c 0.14, EtOH) 1-66

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(6-methyl pyridin-3-yl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.34(3H, s), 3.25-3.34 (1H, m), 3.44 (1H, t, J = 9.8 Hz), 3.75 (3H, s),3.77-3.85 (1H, m), 4.56 (1H, dd, J = 10.7, 8.3 Hz), 6.57 (1H, d, J = 8.6Hz), 6.74 (2H, d, J = 11.0 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.68 (1H, dd,J = 8.6, 2.4 Hz), 8.05 (1H, s), 8.34 (1H, d, J = 2.4 Hz), 8.72 (1H, s).MS (ESI⁺) m/z: 377 (MH⁺). [α] _(D) ²⁴ = −168 (c 0.22, EtOH) 1-67

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-[6-(trifluoro- methyl)pyridin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆)δ 3.25-3.35 (1H, m), 3.40-3.50 (1H, m), 3.75 (3H, s) , 3.81-3.90 (1H,m), 4.59 (1H, dd, J = 10.7, 8.3 Hz), 6.74 (2H, d, J = 11.0 Hz), 6.84(1H, d, J = 8.6 Hz), 7.71 (1H, d, J = 9.2 Hz), 8.06-8.11 (2H, m), 8.62(1H, d, J = 2.4 Hz), 9.36 (1H, s). MS (ESI⁺) m/z: 431 (MH⁺). [α] _(D) ²⁴= −236 (c 0.20, EtOH)

TABLE 69 Ex. No. Str. Chemical name P. D. 1-68

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(3- hydroxy-4- methylphenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ1.98 (3H, s), 3.26-3.33 (1H, m), 3.40-3.47 (1H, m), 3.70-3.79 (1H, m),3.75 (3H, s), 4.56 (1H, dd, J = 10.7, 8.3 Hz), 6.31 (1H, d, J = 7.9 Hz),6.54 (1H, dd, J = 8.6, 2.4 Hz), 6.73 (2H, d, J = 11.0 Hz), 6.81 (1H, d,J = 8.6 Hz), 6.97 (1H, d, J = 2.4 Hz), 8.05 (1H, s), 8.39 (1H, s), 9.08(1H, s). MS (ESI⁺) m/z: 392 (MH⁺). [α] _(D) ²⁵ = −198 (c 0.15, EtOH)1-69

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(2- fluoro-4-methyl- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ2.21 (3H, s), 3.26-3.33 (1H, m), 3.46 (1H, t, J = 9.5 Hz), 3.66-3.74(1H, m), 3.75 (3H, s), 4.56 (1H, dd, J = 10.7, 8.3 Hz), 6.74 (2H, d, J =11.0 Hz), 6.82-6.86 (2H, m), 6.97 (1H, d, J = 12.8 Hz), 7.78 (1H, t, J =8.3 Hz), 8.10 (1H, s), 8.27 (1H, s). MS (ESI⁺) m/z: 394 (MH⁺). [α] _(D)²⁶ = −188 (c 0.12, EtOH) 1-70

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(2,3- dihydro-1H-inden- 5-yl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ1.90-1.99 (2H, m), 2.74 (4H, q, J = 7.7 Hz), 3.26-3.33 (1H, m), 3.44(1H, t, J = 9.2 Hz), 3.72-3.80 (1H, m), 3.75 (3H, s), 4.56 (1H, dd, J =11.0, 8.6 Hz), 6.37 (1H, td J = 8.6 Hz), 6.73 (2H, d, J = 11.0 Hz),6.97-7.03 (2H, m), 7.25 (1H, s), 8.04 (1H, s), 8.45 (1H, s). MS (ESI⁺)m/z: 402 (MH⁺). [α] _(D) ²⁶ = −186 (c 0.26, EtOH)

TABLE 70 Ex. No. Str. Chemical name P. D. 1-71

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(4-fluoro- 3-hydroxy- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.26-3.33 (1H, m), 3.43 (1H, t, J = 9.5 Hz), 3.73-3.81 (1H, m), 3.75(3H, s) , 4.56 (1H, dd, J = 10.7, 8.3 Hz), 6.36 (1H, d, J = 8.6 Hz),6.58-6.62 (1H, m), 6.73 (2H, d, J = 11.0 Hz), 6.90 (1H, dd, J = 11.0,9.2 Hz), 7.12 (1H, dd, J = 7.9, 2.4 Hz), 8.05 (1H, s), 8.54 (1H, s),9.65 (1H, s). MS (ESI⁺) m/z: 396 (MH⁺). [α] _(D) ²⁶ = −188 (c 0.12,EtOH) 1-72

(−)-1-(4-chloro-3- hydroxyphenyl)-3- [(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.26-3.33 (1H, m), 3.44 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.76-3.82(1H, m), 4.56 (1H, dd, J = 10.7, 8.3 Hz), 6.42 (1H, d, J = 8.6 Hz), 6.66(1H, dd, J = 8.6, 2.4 Hz), 6.73 (2H, d, J = 11.0 Hz), 7.07 (1H, d, J =8.6 Hz), 7.21 (1H, d, J = 2.4 Hz), 8.07 (1H, s), 8.67 (1H, s), 9.95 (1H,s). MS (ESI⁺) m/z: 412 (MH⁺). [α] _(D) ²⁶ = −189 (c 0.18, EtOH) 1-73

1-(4-cyano-3- hydroxyphenyl)- 3-[(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.26-3.33 (1H, m), 3.44 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.76-3.84(1H, m), 4.57 (1H, dd, J = 11.0, 8.6 Hz), 6.61 (1H, d, J = 7.9 Hz),6.71-6.76 (3H, m), 7.29 (1H, s), 7.35 (1H, d, J = 8.6 Hz), 8.09 (1H, s),9.08 (1H, s), 10.81 (1H, brs). MS (ESI⁺) m/z: 403 (MH⁺).

TABLE 71 Ex. No. Str. Chemical name P. D. 1-74

1-{(3S*,4R*)-4- [4-(difluoro- methoxy)-2,6- difluorophenyl]-2-oxopyrrolidin- 3-yl}-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.28-3.34 (1H, m), 3.46-3.50 (1H, m), 3.86 (1H, q, J = 9.7Hz), 4.57 (1H, dd, J = 10.9, 7.9 Hz), 6.48 (1H, d, J = 8.5 Hz),6.99-7.08 (4H, m), 7.30-7.33 (2H, m), 7.32 (1H, t, J = 73.3 Hz), 8.09(1H, br), 8.70 (1H, s). MS (ESI⁺) m/z: 416 (MH⁺). 1-75

(−)-1-[(3S*,4R*)- 4-(4-ethoxy-2,6- difluorophenyl)- 2-oxopyrrolidin-3-yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, CDCl₃) δ 1.29 (3H, t, J =7.0 Hz), 3.25-3.34 (1H, m), 3.44 (1H, t, J = 9.2 Hz), 3.75-3.82 (1H, m),4.02 (2H, q, J = 7.0 Hz), 4.54 (1H, dd, J = 10.4, 8.3 Hz), 6.68-6.75(1H, m), 6.71 (2H, d, J = 11.0 Hz), 7.01 (2H, t, J = 9.0 Hz), 7.34 (2H,dd, J = 9.0, 4.9 Hz), 8.03 (1H, s), 8.89 (1H, s) MS (ESI⁺) m/z: 394(MH⁺). [α] _(D) ²⁶ = −149 (c 0.13, EtOH) 1-76

l-{(3S*,4R*)-4- [4-(dimethyl- amino)-2,6- difluorophenyl]-2-oxopyrrolidin-3- yl}-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆)δ 2.87 (6H, s), 3.27 (1H, t, J = 9.8 Hz), 3.39 (1H, t, J = 8.9 Hz), 3.71(1H, q, J = 10.0 Hz), 4.54 (1H, dd, J = 11.0, 8.6 Hz), 6.34 (2H, d, J =12.2 Hz), 6.52 (1H, d, J = 9.2 Hz), 6.98-7.04 (2H, m), 7.31-7.37 (2H,m), 7.99 (1H, s), 8.71 (1H, s). MS (ESI⁺) m/z: 393 (MH⁺).

TABLE 72 Ex. No. Str. Chemical name P. D. 1-77

(−)-1-[(3S*,4R*)- 4-(6-fluorobenzo- furan-5-yl)-2- oxopyrrolidin-3-yl]-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.21-3.26 (1H,m), 3.51-3.55 (1H, m), 3.80-3.87 (1H, m), 4.65 (1H, dd, J = 11.3, 8.8Hz), 6.77 (1H, d, J = 8.8 Hz), 6.94 (1H, d, J = 2.4 Hz), 7.00 (2H, t, J= 9.0 Hz), 7.34 (2H, dd, J = 9.0, 4.9 Hz), 7.54 (1H, d, J = 11.0 Hz),7.80 (1H, d, J = 7.3 Hz), 7.97 (1H, s), 7.99 (1H, d, J = 2.4 Hz), 8.87(1H, s). MS (ESI⁺) m/z: 372 (MH⁺). [α] _(D) ²⁵ = −201 (c 0.10, EtOH)1-78

(−)-1-(4-fluoro- phenyl)-3- [(3S*,4R*)-4-(6- methoxypyridin-3-yl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.17-3.24(1H, m), 3.42-3.52 (2H, m), 3.80 (3H, s), 4.47-4.52 (1H, m), 6.60 (1H,brs), 6.79 (1H, d, J = 8.6 Hz), 7.02 (2H, dd, J = 9.2, 8.6 Hz), 7.35(2H, dd, J = 9.2, 4.9 Hz), 7.80 (1H, dd, J = 8.6, 2.4 Hz), 7.95 (1H, s),8.10 (1H, d, J = 2.4 Hz), 8.75 (1H, brs). MS (ESI⁺) m/z: 345 (MH⁺). [α]_(D) ²⁶ = −103 (c 0.12, EtOH) 1-79

(−)-N-(3,5-difluoro- 4-{(3R*,4S*)-4-[3- (4-fluoro- phenyl)ureido]-5-oxopyrrolidin-3- yl}phenyl)acetamide ¹H-NMR (400 MHz, DMSO-d₆) δ 2.03(3H, s), 3.28-3.35 (1H, m), 3.42-3.48 (1H, m), 3.81 (1H, q, J = 9.8 Hz),4.56 (1H, dd, J = 10.7, 8.3 Hz), 6.46 (1H, d, J = 8.6 Hz), 6.97-7.04(2H, m), 7.25-7.34 (4H, m), 8.06 (1H, s), 8.67 (1H, s), 10.26 (1H, s).MS (ESI⁺) m/z: 407 (MH⁺). [α] _(D) ²⁴ = −31 (c 0.12, EtOH)

TABLE 73 Ex. No. Str. Chemical name P. D. 1-80

1-[(3S*,4R*)-4- (4,6-difluoro-2,3- dihydrobenzo- furan-5-yl)-2-oxopyrrolidin-3- yl]-3-(4-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆)δ 3.18 (2H, t, J = 8.6 Hz), 3.28 (1H, t, J = 9.5 Hz), 3.42 (1H, t, J =9.2 Hz), 3.79 (1H, q, J = 9.8 Hz), 4.55 (1H, dd, J = 10.4, 8.6 Hz), 4.62(2H, t, J = 8.6 Hz), 6.48 (1H, d, J = 8.6 Hz), 6.62 (1H, d, J = 11.0Hz), 6.99-7.05 (2H, m), 7.31-7.37 (2H, m), 8.03 (1H, s), 8.68 (1H, s).MS (ESI⁺) m/z: 392 (MH⁺). 1-81

1-[(3S*,4R*)-4-(6- fluoro-1-hydroxy- 2,3-dihydro-1H- inden-5-yl)-2-oxopyrrolidin-3- yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ1.74-1.81 (1H, m), 2.28-2.36 (1H, m), 2.62-2.69 (1H, m), 2.79-2.86 (1H,m), 3.18 (1H, t, J = 9.5 Hz), 3.46 (1H, t, J = 8.9 Hz), 3.74 (1H, q, J =10.0 Hz), 4.57 (1H, dd, J = 11.3, 8.9 Hz), 4.98 (1H, q, J = 6.3 Hz),5.28 (1H, t, J = 5.2 Hz), 6.66 (1H, d, J = 8.6 Hz), 6.99-7.05 (3H, m),7.33-7.38 (3H, m), 7.95 (1H, s), 8.79 (1H, s). MS (ESI⁺) m/z: 388 (MH⁺).1-82

1-[(3S*,4R*)-4- (6-fluoro-2,3- dihydro-1H-inden- 5-yl)-2-oxopyrrolidin-3- yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ1.96-2.04 (2H, m), 2.80 (4H, q, J = 8.2 Hz), 3.18 (1H, t, J = 9.8 Hz),3.45 (1H, d, J = 8.9 Hz), 3.72 (1H, q, J = 9.8 Hz), 4.56 (1H, dd, J =11.3, 8.9 Hz), 6.54 (1H, d, J = 7.9 Hz), 6.99-7.05 (3H, m), 7.32-7.37(3H, m), 7.94 (1H, s), 8.69 (1H, s). MS (ESI⁺) m/z: 372 (MH⁺).

TABLE 74 Ex. No. Str. Chemical name P. D. 1-83

(−)-1-[(3S*,4R*)- 4-(6-fluoro-2,3- dihydrobenzo- furan-5-yl)-2-oxo-pyrrolidin-3-yl]- 3-(p-tolyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.19 (3H,s), 3.11 (2H, t, J = 8.6 Hz), 3.15 (1H, t, J = 9.5 Hz), 3.42 (1H, t, J =8.9 Hz), 3.61-3.68 (1H, m), 4.50-4.56 (3H, m), 6.46 (1H, brs), 6.62 (1H,d, J = 11.0 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.6 Hz),7.37 (1H, d, J = 7.3 Hz), 7.92 (1H, s), 8.52 1H, brs). MS (ESI⁺) m/z:370 (MH⁺). [α] _(D) ²⁸ = −158 (c 0.20, EtOH) 1-84

(−)-1-(4-cyano- phenyl)-3- [(3S*,4R*)-4-(6- fluoro-2,3- dihydrobenzo-furan-5-yl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.04-3.21 (3H, m), 3.43 (1H, t, J = 8.9 Hz), 3.66-3.73 (1H, m),4.51-4.56 (3H, m), 6.63 (1H, d, J = 11.6 Hz), 7.29 (1H, brs), 7.36 (1H,d, J = 7.9 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 8.6 Hz), 7.94(1H, s), 9.70 (1H, brs). MS (ESI⁺) m/z: 381 (MH⁺). [α] _(D) ²⁷ = -138 (c0.12, EtOH) 1-85

(−)-1- (benzo[b]thiophen- 2-yl)-3- [(3S*,4R*)-4-(6- fluoro-2,3-dihydro-benzofuran-5-yl)- 2-oxopyrrolidin-3- yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.12 (2H, t, J = 8.6 Hz), 3.18 (1H, t, J = 9.8 Hz), 3.44 (1H, t, J = 9.8Hz), 3.69-3.76 (1H, m), 4.52-4.56 (3H, m), 6.62-6.64 (2H, m), 7.01 (1H,brs), 7.07 (1H, dd, J = 7.9, 7.4 Hz), 7.20 (1H, dd, J = 7.9, 7.4 Hz),7.39 (1H, d, J = 7.9 Hz), 7.50 (1H, d, J = 7.9 Hz), 7.68 (1H d, J = 7.9Hz), 7.95 (1H, s), 10.21 (1H, brs). MS (ESI⁺) m/z: 412 (MH⁺). [α] _(D)²⁵ = −128 (c 0.14, EtOH)

TABLE 75 Ex. No. Str. Chemical name P. D. 1-86

(+)-1-[(3R*,4S*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-(p-tolyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.18 (3H,s), 3.29-3.49 (2H, m), 3.71-3.78 (1H, m), 3.75 (3H, s), 4.56 (1H, dd, J= 11.0, 8.6 Hz), 6.41 (1H, brd, J = 8.6 Hz), 6.73 (2H, d, J = 11.0 Hz),6.98 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz), 8.04 (1H, s), 8.51(1H, s). MS (ESI⁺) m/z: 376 (MH⁺). [α] _(D) ²⁵ +108 (c 0.13, EtOH) 1-87

(+)-1-[(3R*,4S*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-phenylurea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.30 (1H, t,J = 9.8 Hz), 3.45 (1H, t, J = 9.8 Hz), 3.75 (3H, s), 3.76-3.82 (m, 1H),4.57 (1H, dd, J = 11.0, 8.6 Hz), 6.46 (1H, d, J = 8.6 Hz), 6.74 (2H, d,J = 11.0 Hz), 6.86 (1H, t, J = 7.3 Hz), 7.18 (2H, dd, J = 8.6, 7.3 Hz),7.32 (2H, d, J = 8.6 Hz), 8.06 (1H, s), 8.62 (1H, s). MS (ESI⁺) m/z: 362(MH⁺). [α] _(D) ²⁴ = +153 (c 0.10, EtOH)

Example 2-1

(+)-trans-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]urea(−)-trans-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]urea

The same method as in Example 1-1 was performed using(±)-trans-4-(4-methoxyphenyl)-5,5-dimethyl-2-oxopyrrolidine-3-carboxylicacid in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid toobtain(±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]urea.

The obtained(±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]ureawas subjected to optical resolution by high performance liquidchromatography (methyl tert-butyl ether:ethanol=4:1, flow rate: 15.0 mL)using a column for separation of enantiomers (Daicel Corporation,CHIRALPAK ID). An isomer A(+) with a retention time of 6.94 minutes andan isomer B (−) with a retention time of 16.14 minutes that were thetitle compounds were each obtained as a white solid.

Isomer A(+):

¹H-NMR (400 MHz, DMSO-d₆) δ 0.78 (3H, s), 1.22 (3H, s), 3.26 (1H, d,J=12.1 Hz), 3.72 (3H, s), 4.88 (1H, dd, J=12.1, 9.1 Hz), 6.31 (1H, d,J=9.1 Hz), 6.89 (2H, d, J=8.5 Hz), 7.02 (2H, t, J=9.1 Hz), 7.25 (2H, d,J=8.5 Hz), 7.34 (2H, dd, J=9.1, 4.8 Hz), 8.01 (1H, s), 8.48 (1H, s).

MS (ESI⁺) m/z: 372 (MH⁺).

[α]_(D) ²⁵=+133 (c 0.21, CHCl₃)

Isomer B(−):

¹H-NMR (400 MHz, DMSO-d₆) δ 0.78 (3H, s), 1.22 (3H, s), 3.26 (1H, d,J=12.1 Hz), 3.72 (3H, s), 4.88 (1H, dd, J=12.1, 9.1 Hz), 6.31 (1H, d,J=9.1 Hz), 6.89 (2H, d, J=8.5 Hz), 7.02 (2H, t, J=9.1 Hz), 7.25 (2H, d,J=8.5 Hz), 7.34 (2H, dd, J=9.1, 4.8 Hz), 8.01 (1H, s), 8.48 (1H, s).

MS (ESI⁺) m/z: 372 (MH⁺).

[α]_(D) ²⁵=−147 (c 0.21, CHCl₃)

Example 3-1

(+)-trans-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea(−)-trans-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea

The same method as in Example 1-1 was performed using(±)-trans-4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonane-3-carboxylicacid in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid toobtain (±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea. The obtained(±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea was subjected to optical resolution by highperformance liquid chromatography (methyl tert-butyl ether:ethanol=4:1,flow rate: 20.0 mL) using a column for separation of enantiomers(CHIRALPAK ID). An isomer A(+) with a retention time of 9.02 minutes andan isomer B(−) with a retention time of 14.27 minutes that were thetitle compounds were each obtained as a white solid.

Isomer A(+):

¹H-NMR (400 MHz, DMSO-d6) δ 1.05-1.81 (8H, m), 3.45 (1H, d, J=12.1 Hz),3.71 (3H, s), 4.82 (1H, dd, J=12.1, 9.1 Hz), 6.31 (1H, d, J=9.1 Hz),6.88 (2H, d, J=9.1 Hz), 7.02 (2H, t, J=9.1 Hz), 7.25 (2H, d, J=9.1 Hz),7.34 (2H, dd, J=9.1, 4.8 Hz), 8.28 (1H, s), 8.47 (1H, s).

MS (ESI⁺) m/z: 398 (MH⁺).

HRMS (ESI⁺) for C₂₂H₂₅FN₃O₃(MH⁺): calcd, 398.18799; found, 398.18738.

[α]_(D) ²⁴=+124 (c 0.31, CHCl₃).

Isomer B(−):

¹H-NMR (400 MHz, DMSO-d₆) δ 1.05-1.81 (8H, m), 3.45 (1H, d, J=12.1 Hz),3.71 (3H, s), 4.82 (1H, dd, J=12.1, 9.1 Hz), 6.31 (1H, d, J=9.1 Hz),6.88 (2H, d, J=9.1 Hz), 7.02 (2H, t, J=9.1 Hz), 7.25 (2H, d, J=9.1 Hz),7.34 (2H, dd, J=9.1, 4.8 Hz), 8.28 (1H, s), 8.47 (1H, s).

MS (ESI⁺) m/z: 398 (MH⁺).

HRMS (ESI⁺) for C₂₂H₂₅FN₃O₃(MH⁺): calcd, 398.18799; found, 398.18880.

[α]_(D) ²⁴=−125 (c 0.31, CHCl₃).

Example 4-1

(+)-trans-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea(−)-trans-1-(4-Fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea

The same method as in Example 1-1 was performed using(±)-trans-4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decane-3-carboxylicacid in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid toobtain (±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea. The obtained(±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea was subjected to optical resolution by highperformance liquid chromatography (methyl tert-butylether:ethanol=85:15, flow rate: 15.0 mL) using a column for separationof enantiomers (CHIRALPAK ID). An isomer A(+) with a retention time of12.16 minutes and an isomer B(−) with a retention time of 17.07 minutesthat were the title compounds were each obtained as a white solid.

Isomer A(+):

¹H-NMR (400 MHz, DMSO-d₆) δ 0.55-0.67 (1H, m), 0.76-0.92 (1H, m),1.29-1.71 (8H, m), 3.14 (1H, d, J=12.2 Hz), 3.72 (3H, s), 4.89 (1H, dd,J=12.2, 8.6 HzH), 6.31 (1H, d, J=8.6 Hz), 6.88 (2H, d, J=8.6 Hz), 7.02(2H, t, J=8.8 Hz), 7.25 (2H, d, J=8.5 Hz), 7.34 (2H, dd, J=9.1, 4.8 Hz),8.01 (1H, s), 8.48 (1H, s).

MS (ESI⁺) m/z: 412 (MH⁺).

HRMS (ESI⁺) for C₂₃H₂₇FN₃O₃(MH⁺): calcd, 412.20364; found, 412.20364.

[α]_(D) ²⁵=+133 (c 0.32, CHCl₃).

Isomer B(−):

¹H-NMR (400 MHz, DMSO-d₆) δ 0.55-0.67 (1H, m), 0.76-0.92 (1H, m),1.29-1.71 (8H, m), 3.14 (1H, d, J=12.2 Hz), 3.72 (3H, s), 4.89 (1H, dd,J=12.2, 8.6 Hz), 6.31 (1H, d, J=8.6 Hz), 6.88 (2H, d, J=8.6 Hz), 7.02(2H, t, J=8.8 Hz), 7.25 (2H, d, J=8.5 Hz), 7.34 (2H, dd, J=9.1, 4.8 Hz),8.01 (1H, s), 8.48 (1H, s).

MS (ESI⁺) m/z: 412 (MH⁺).

HRMS (ESI⁺) for C₂₃H₂₇FN₃O₃(MH⁺): calcd, 412.20364; found, 412.20416.

[α]_(D) ²⁵=−137 (c 0.31, CHCl₃).

Example 5-1

(−)-1-(4-Fluorophenyl)-3-[(3S*,4R*)-4-(4-methylsulfinylphenyl)-2-oxopyrrolidin-3-yl]urea

Meta-chloroperoxybenzoic acid (mCPBA) (70 mg) was added to a solution of1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylthiophenyl)-2-oxopyrrolidin-3-yl]urea(100 mg) in dichloromethane (5 mL) to produce a reaction solution. Thereaction solution was stirred at room temperature for 1 hour. Asaturated sodium hydrogen carbonate solution was added to the reactionsolution, and the mixture was extracted with a dichloromethane-methanolmixed solution. The extract was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate:methanol=5:1), to obtainthe title compound as a white solid (85 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.71 (3H, s), 3.23 (1H, t, J=9.4 Hz),3.50-3.68 (2H, m), 4.55 (1H, dd, J=11.5, 8.5 Hz), 6.47 (1H, d, J=8.5Hz), 7.00-7.05 (2H, m), 7.32-7.37 (2H, m), 7.58-7.64 (4H, m), 7.97 (1H,s), 8.59 (1H, s).

MS (ESI⁺) m/z: 376 (MH⁺).

[α]_(D) ²⁶=−168 (c 0.14, EtOH).

Example 6-1

(−)-1-(4-Fluorophenyl)-3-[(3S*,4R*)-4-(4-methylsulfonylphenyl)-2-oxopyrrolidin-3-yl]urea

Meta-chloroperoxybenzoic acid (mCPBA) (140 mg) was added to a solutionof1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylthiophenyl)-2-oxopyrrolidin-3-yl]urea(84 mg) in dichloromethane (5 mL) to produce a reaction solution. Thereaction solution was stirred at room temperature for 1 hour. Asaturated sodium hydrogen carbonate solution was added to the reactionsolution, and the mixture was extracted with a dichloromethane-methanolmixed solution. The extract was washed with water and a brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate:methanol=5:1), to obtainthe title compound as a white solid (67 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ3.19 (3H, s), 3.25 (1H, t, J=9.7 Hz), 3.55(1H, t, J=8.5 Hz), 3.64-3.72 (1H, m), 4.57 (1H, dd, J=10.9, 8.5 Hz),6.49 (1H, d, J=8.5 Hz), 7.00-7.05 (2H, m), 7.32-7.36 (2H, m), 7.68 (2H,d, J=8.5 Hz), 7.87 (2H, d, J=8.5 Hz), 8.00 (1H, s), 8.61 (1H, s).

MS (ESI⁺) m/z: 392 (MH⁺).

[α]_(D) ²⁶=−189 (c 0.14, EtOH).

Example 7-1

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(trifluoromethoxy)phenyl]urea

4-(Trifluoromethoxy)phenyl isocyanate (36 μL) was added to a solution of(−)-(3S*,4R*)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one(58 mg) in tetrahydrofuran (2.4 mL) to produce a reaction solution. Thereaction solution was stirred at room temperature for 30 minutes. Thereaction solution was concentrated, and the residue was then purified bysilica gel column chromatography (hexane:ethyl acetate=9:1 followed byethyl acetate), to obtain the title compound as a white solid (94 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.27-3.31 (1H, m), 3.44 (1H, t, J=9.2 Hz),3.74 (3H, s), 3.76-3.84 (1H, m), 4.57 (1H, dd, J=10.4, 8.6 Hz), 6.56(1H, d, J=8.6 Hz), 6.74 (2H, d, J=10.4 Hz), 7.18 (2H, d, J=8.6 Hz), 7.14(2H, d, J=8.6 Hz), 8.06 (1H, s), 8.89 (1H, s).

MS (ESI⁺) m/z: 446 (MH⁺).

[α]_(D) ²⁷=−150 (c 0.10, EtOH).

The same method as in Example 7-1 was performed using a correspondingisocyanate to obtain the following Examples 7-2 to 7-14.

The structures and spectral data thereof are shown in Tables 76 to 80.

TABLE 76 Ex. No Str. Chemical name P. D. 7-2

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxo-pyrrolidin-3-yl]- 3-phenylurea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.30 (1H, t,J = 9.8 Hz), 3.45 (1H, t, J = 9.8 Hz), 3.75 (3H, s), 3.76-3.82 (m, 1H),4.57 (1H, dd, J = 11.0, 8.6 Hz), 6.46 (1H, d, J = 8.6 Hz), 6.74 (2H, d,J = 11.0 Hz), 6.86 (1H, t, J = 7.3 Hz), 7.18 (2H, dd, J = 8.6, 7.3 Hz),7.32 (2H, d, J = 8.6 Hz), 8.06 (1H, s), 8.62 (1H, s). MS (ESI⁺) m/z: 362(MH⁺). [α] _(D) ²⁷ = −162 (c 0.10, EtOH) 7-3

(−)-1-[4-(tert- butyl)phenyl]-3- [(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ1.21 (9H, s), 3.27-3.48 (2H, m), 3.71-3.80 (1H, m), 3.74 (3H, s), 4.56(1H, dd, J = 11.0, 8.0 Hz), 6.39 (1H, d, J = 8.0 Hz), 6.73 (2H, d, J =11.0 Hz), 7.17-7.23 (4H, m), 8.04 (1H, s), 8.51 (1H, s). MS (ESI⁺) m/z:418 (MH⁺). [α] _(D) ²⁷ = −117 (c 0.11, EtOH) 7-4

(−)-4-{(3S*,4R*)- 3-[4-(2,6-difluoro- 4-methoxy- phenyl)-2-oxopyrrolidin-3- yl]ureido}benzoic acid ethyl ester ¹H-NMR (400 MHz,DMSO-d₆) δ 1.28 (3H, t, J = 6.8 Hz), 3.28-3.39 (1H, m), 3.45 (1H, t, J =9.2 Hz), 3.75 (3H, s), 3.78-3.86 (1H, m), 4.23 (2H, q, J = 6.8 Hz), 4.57(1H, dd, J = 10.4, 8.6 Hz), 6.66 (1H, d, J = 8.6 Hz), 6.74 (2H, d, J =10.4 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.79 (2H, d, J = 8.6 Hz), 8.08 (1H,s), 9.13 (1H, s). MS (ESI⁺) m/z: 434 (MH⁺). [α] _(D) ²⁷ = −161 (c 0.10,EtOH)

TABLE 77 Ex. No Str. Chemical name P. D. 7-5

(−)-1-[(1,1′- biphenyl)-4-yl]- 3-[(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.29-3.34 (1H, m), 3.46 (1H, t, J = 8.6 Hz), 3.75 (3H, s), 3.81 (1H, q,J = 8.6 Hz), 4.59 (1H, dd, J = 8.6, 8.6 Hz), 6.51 (1H, d, J = 8.6 Hz),6.74 (2H, d, J = 10.4 Hz), 7.28 (1H, t, J = 7.3 Hz), 7.38-7.43 (4H, m),7.50 (2H, d, J = 9.2 Hz), 7.58 (2H, d, J = 8.0 Hz), 8.07 (1H, s), 8.75(1H, s). MS (ESI⁺) m/z: 438 (MH⁺). [α] _(D) ²⁷ = −168 (c 0.10, EtOH) 7-6

(−)-1-(4-acetyl- phenyl)-3- [(3S*,4R*)-4- (2,6-difluoro-4-methoxyphenyl)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ2.45 (3H, s), 3.26-3.31 (1H, m), 3.44 (1H, t, J = 9.2 Hz), 3.74 (3H, s),3.81 (1H, q, J = 9.2 Hz), 4.57 (1H, dd, J = 9.2, 8.6 Hz), 6.65 (1H, d, J= 8.6 Hz), 6.73 (2H, d, J = 10.4 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.80(2H, d, J = 8.6 Hz), 8.07 (1H, s), 9.11 (1H, s). MS (ESI⁺) m/z: 404(MH⁺). [α] _(D) ²⁷ = −153 (c 0.10, EtOH) 7-7

(−)-1-[(3S*,4R*)- 4-[2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(4-phenoxy- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.30 (1H, t, J= 9.2 Hz), 3.44 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.79 (1H, q, J = 9.2Hz), 4.57 (1H, t, J = 8.6 Hz), 6.47 (1H, d, J = 8.6 Hz), 6.74 (2H, d, J= 11.0 Hz), 6.88-6.91 (4H, m), 7.05 (1H, t, J = 7.3 Hz), 7.30-7.35 (4H,m), 8.05 (1H, s), 8.67 (1H, s). MS (ESI⁺) m/z: 454 (MH⁺). [α] _(D) ²⁷ =−163 (c 0.10, EtOH)

TABLE 78 Ex. No Str. Chemical name P. D. 7-8

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(3-fluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.28-3.33 (1H,m), 3.40-3.49 (1H, m), 3.75 (3H, s), 3.81 (1H, q, J = 9.5 Hz), 4.56 (1H,dd, J = 11.0, 8.0 Hz), 6.57 (1H, d, J = 8.0 Hz), 6.64-6.70 (1H, m), 6.74(2H, d, J = 10.4 Hz),7.00 (1H, d, J = 8.6 Hz), 7.17-7.23 (1H, m),7.32-7.37 (1H, m), 8.07 (1H, s), 8.90 (1H, s). MS (ESI⁺) m/z: 380 (MH⁺).[α] _(D) ²⁷ = −152 (c 0.10, EtOH) 7-9

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(3,4-difluoro- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.27-3.36(1H, m), 3.40-3.48 (1H, m), 3.75 (3H, s), 3.81 (1H, q, J = 9.2 Hz), 4.56(1H, dd, J = 9.2, 8.6 Hz), 6.60 (1H, d, J = 8.6 Hz), 6.74 (2H, d, J =11.0 Hz), 6.97-7.03 (1H, m), 7.20-7.27 (1H, m), 7.49-7.56 (1H, m), 8.06(1H, s), 8.91 (1H, s). MS (ESI⁺) m/z: 398 (MH⁺). [α] _(D) ²⁷ = −138 (c0.10, EtOH)

TABLE 79 Ex. No Str. Chemical name P. D. 7-10

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(4-ethyl- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 1.11 (3H, t, J= 7.4 Hz), 2.49 (2H, q, J = 7.4 Hz), 3.30 (1H, t, J = 9.2 Hz), 3.44 (1H,t, J = 9.2 Hz), 3.75 (3H, s), 3.77 (1H, q, J = 9.2 Hz), 4.56 (1H, dd, J= 10.4, 8.6 Hz), 6.42 (1H, d, J = 8.6 Hz), 6.73 (2H, d, J = 10.4 Hz),7.01 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.6 Hz), 8.05 (1H, s), 8.53(1H, s). MS (ESI⁺) m/z: 390 (MH⁺). [α] _(D) ²⁷ = −134 (c 0.10, EtOH)7-11

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3- (m-tolyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.20 (3H, s),3.27-3.33 (1H, m), 3.44 (1H, t, J = 9.5 Hz), 3.75 (3H, s), 3.76-3.82(1H, m), 4.56 (1H, dd, J = 10.7, 8.3 Hz), 6.43 (1H, d, J = 7.9 Hz), 6.69(1H, d, J = 6.7 Hz), 6.73 (2H, d, J = 11.0 Hz), 7.02-7.10 (2H, m), 7.18(1H, s), 8.05 (1H, s), 8.53 (1H, s). MS (ESI⁺) m/z: 376 (MH⁺). [α] _(D)²⁵ = −135 (c 0.22, EtOH) 7-12

(−)-1-(3-cyano- phenyl)-3-[(3S*,4R*)- 4-(2,6-difluoro-4-methoxyphenyl)-2- oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.25-3.35 (1H, m), 3.40-3.50 (1H, m), 3.75 (3H, s), 3.78-3.87 (1H, m),4.57 (1H, dd, J = 10.7, 8.3 Hz), 6.74 (2H, d, J = 11.0 Hz), 7.30-7.33(1H, m), 7.40 (1H, t, J = 7.9 Hz), 7.52-7.57 (1H, m), 7.85 (1H, s), 8.07(1H, s), 9.08 (1H, s). MS (ESI⁺) m/z: 387 (MH⁺). [α] _(D) ²⁵ = −86 (c0.13, EtOH)

TABLE 80 Ex. No Str. Chemical name P. D. 7-13

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]-3-(3- methoxy- phenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.27-3.33(1H, m), 3.44 (1H, t, J = 9.5 Hz), 3.67 (3H, s), 3.75 (3H, s), 3.80 (1H,t, J = 9.8 Hz), 4.56 (1H, dd, J = 11.0, 8.6 Hz), 6.43-6.47 (2H, m), 6.74(2H, d, J = 11.0 Hz), 6.80-6.83 (1H, m), 7.04-7.10 (2H, m), 8.05 (1H,s), 8.63 (1H, s). MS (ESI⁺) m/z: 392 (MH⁺). [α] _(D) ²⁶ = −173 (c 0.14,EtOH) 7-14

(−)-1-[(3S*,4R*)- 4-(3-fluoro-5- methoxypyridin- 2-yl)-2-oxo-pyrrolidin-3-yl]- 3-(p-tolyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.18 (3H,s), 3.38 (1H, t, J = 9.5 Hz), 3.47 (1H, t, J = 9.2 Hz), 3.83 (3H, s),3.90-4.01 (1H, m), 4.50 (1H, dd, J = 10.1, 8.3 Hz), 6.51 (1H, d, J = 7.3Hz), 6.98 (2H, J = 8.3 Hz), 7.20 (2H, d, J = 8.3 Hz), 7.38 (1H, dd, J =12.2, 2.4 Hz), 7.93 (1H, s), 8.20 (1H, d, J = 2.4 Hz), 8.53 (1H, s). MS(ESI⁺) m/z: 359 (MH⁺). [α] _(D) ²⁶ = −177 (c 0.10, EtOH)

Example 8-1

(−)-1-(5-Chlorothiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea

Triethylamine (51 μL) and diphenylphosphoryl azide (83 μL) were added toa solution of 5-chlorothiophene-2-carboxylic acid (60 mg) in toluene(3.7 mL) to produce a reaction solution. The reaction solution wasstirred at room temperature for 3 hours. The reaction temperature washeated up to 100° C., and the reaction solution was then stirred for 1hour.

(−)-(3S*,4R*)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one(71 mg) was added and the reaction solution was stirred at 100° C. for 1hour. The reaction solution was concentrated, and the residue was thenpurified by silica gel column chromatography (hexane:ethyl acetate=4:1followed by ethyl acetate), to obtain the title compound as a whitesolid (45 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.27-3.31 (1H, m), 3.44 (1H, t, J=9.2 Hz),3.75 (3H, s), 3.80-3.88 (1H, m), 4.52 (1H, dd, J=11.0, 9.2 Hz), 6.20(1H, d, J=4.3 Hz), 6.71-6.81 (4H, m), 8.06 (1H, s), 9.94 (1H, s).

MS (ESI⁺) m/z: 402 (MH⁺).

[α]_(D) ²⁷=−135 (c 0.11, EtOH)

The same method as in Example 8-1 was performed using a correspondingcarboxylic acid substance and amine to obtain the following Examples 8-2to 8-3. The structures and spectral data thereof are shown in Table 81.

TABLE 81 Ex. No Str. Chemical name P. D. 8-2

(−)-1-(5-chloro- thiophen-2-yl)- 3-[(3S*,4R*)- 4-(3-fluoro-5-methoxypyridin- 2-yl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.30-3.37 (1H, m), 3.46 (1H, t, J = 8.9 Hz), 3.83 (3H, s),3.96-4.03 (1H, m), 4.48 (1H, d, J = 10.4 Hz), 6.05-6.15 (1H, m), 6.66(1H, d, J = 4.3 Hz), 7.00-7.30 (1H, m), 7.38 (1H, dd, J = 11.6, 2.4 Hz),7.89 (1H, s), 8.20 (1H, d, J = 2.4 Hz), 10.3-10.6 (1H, m). MS (ESI⁺)m/z: 385 (MH⁺). [α] _(D) ²⁶ = −166 (c 0.10, EtOH) 8-3

(−)-1-(benzo[b] thiophen-2-yl)- 3-[(3S*,4R*)- 4-(3-fluoro-5-methoxypyridin- 2-yl)-2-oxo- pyrrolidin-3- yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.39 (1H, t, J = 9.2 Hz), 3.49 (1H, t, J = 9.2 Hz), 3.83 (3H,s), 4.00-4.07 (1H, m), 4.57 (1H, t, J = 9.2 Hz), 6.65 (1H, s), 6.98-7.06(1H, m), 7.08 (1H, t, J = 7.6 Hz), 7.21 (1H, t, J = 7.6 Hz), 7.38-7.42(1H, m), 7.52 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz), 7.98 (1H,s), 8.20-8.23 (1H, m), 10.19 (1H, s). MS (ESI⁺) m/z: 401 (MH⁺). [α] _(D)²⁷ = −157 (c 0.11, EtOH)

Example 9-1

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(p-tolyl)urea

The same method as in Example 8-1 was performed using 4-methyl benzoicacid in place of 5-chlorothiophene-2-carboxylic acid to obtain the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.18 (3H, s), 3.29-3.49 (2H, m), 3.71-3.78(1H, m), 3.75 (3H, s), 4.56 (1H, dd, J=11.0, 8.6 Hz), 6.41 (1H, brd,J=8.6 Hz), 6.73 (2H, d, J=11.0 Hz), 6.98 (2H, d, J=8.6 Hz), 7.20 (2H, d,J=8.6 Hz), 8.04 (1H, s), 8.51 (1H, s).

MS (ESI⁺) m/z: 376 (MH⁺).

[α]_(D) ²⁷=−144 (c 0.10, EtOH)

Example 10-1

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(hydroxymethyl)phenyl]urea

Diisobutylaluminum hydride (1.0 mL, 1.04 mol/L hexane solution) wasadded to a solution of(−)-4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}benzoicacid ethyl ester (87 mg) in dichloromethane (2.5 mL) under ice-coolingto produce a reaction solution. The reaction solution was stirred atroom temperature for 2.5 hours. A 10% potassium sodium tartrate aqueoussolution and ethyl acetate were added to the reaction solution, and themixture was stirred for 30 minutes and extracted with ethyl acetate. Theorganic layer was washed with a brine, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas then purified by silica gel column chromatography (ethylacetate:methanol=50:1 followed by ethyl acetate:methanol=4:1), to obtainthe title compound as a white solid (66 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.30 (1H, dd, J=9.8, 9.2 Hz), 3.44 (1H, t,J=9.2 Hz), 3.75 (3H, s), 3.75-3.81 (1H, m), 4.36 (2H, d, J=5.5 Hz), 4.56(1H, dd, J=11.0, 8.6 Hz), 4.99 (1H, t, J=5.5 Hz), 6.43 (1H, d, J=7.9Hz), 6.73 (2H, d, J=11.0 Hz), 7.12 (2H, d, J=8.6 Hz), 7.27 (2H, d, J=8.6Hz), 8.05 (1H, s), 8.58 (1H, s).

MS (ESI⁺) m/z: 392 (MH⁺).

[α]_(D) ²⁷=−159 (c 0.10, EtOH)

Example 11-1

(−)-4-{3-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}-N-methylbenzamide

A 2 mol/L sodium hydroxide aqueous solution (0.28 mL) was added to asolution of(−)-4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}benzoicacid ethyl ester (100 mg) in methanol (2.4 mL) to produce a reactionsolution. The reaction solution was stirred at 60° C. for 9 hours. Thereaction solution was concentrated under reduced pressure, a 1 mol/Lhydrochloric acid was added to the residue under ice-cooling to make themixture acidic (pH: 1), and the mixture was extracted with ethylacetate. The organic layer was washed with a brine, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto obtain4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}benzoicacid as an intermediate compound.

2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU) (92 mg) was added to a solutionof the obtained4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}benzoicacid (45 mg), methylamine (45 μL, 12 M/L aqueous solution), anddiisopropyl ethyl amine (DIEA) (40 μL) in N,N-dimethylformamide (1.1 mL)to produce a reaction solution. The reaction solution was stirred atroom temperature for 1 hour. Water was added to the reaction solution,and the mixture was extracted with ethyl acetate. The organic layer waswashed with a brine, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to obtain the title compoundas a white solid (17 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.72 (3H, s), 3.55-3.25 (2H, m), 3.75 (3H,s), 3.76-3.86 (1H, m), 4.52-4.61 (1H, m), 6.61 (1H, brs), 6.70-6.79 (2H,m), 7.34-7.41 (2H, m), 7.63-7.71 (2H, m), 8.07 (1H, s), 8.16-8.23 (1H,brs), 8.93 (1H, brs).

MS (ESI⁻) m/z: 417 (M-H)⁻.

[α]_(D) ²⁸=−159 (c 0.10, DMSO)

Example 12-1

(−)-1-[(3S*,4R*)-1-Ethyl-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

Trifluoroacetic acid (0.4 mL) was added to a solution of[(3S*,4R*)-1-ethyl-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid tert-butylester (63 mg) in dichloromethane (2 mL) to produce areaction solution. The reaction solution was stirred at room temperaturefor 1 hour. The reaction solution was concentrated under reducedpressure, ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the residue to adjust the pH of theaqueous layer to 9. 4-Fluorophenyl isocyanate (20 μL) was added to thesolution of two layers, and the mixture was stirred at room temperaturefor 15 minutes and extracted with ethyl acetate. The organic layer waswashed with water and a brine successively, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was then purified by silica gel column chromatography (ethylacetate:hexane=4:1 followed by ethyl acetate), to obtain the titlecompound as a white solid (48 mg).

¹H-NMR (400 MHz, CDCl₃) δ 1.21 (3H, t, J=7.3 Hz), 3.31-3.45 (2H, m),3.52-3.61 (1H, m), 3.71-3.77 (2H, m), 3.80 (3H, s), 4.24 (1H, dd, J=9.8,6.7 Hz), 6.13 (1H, brs), 6.76 (2H, t, J=8.6 Hz), 6.89 (2H, d, J=8.6 Hz),7.06-7.10 (2H, m), 7.24 (2H, d, J=8.6 Hz), 7.84 (1H, brs).

MS (ESI⁺) m/z: 372 (MH⁺).

[α]_(D) ²⁴=−135 (c 0.30, EtOH).

The same method as in Example 12-1 was performed using a correspondingBoc substance to obtain the following Examples 12-2 to 12-15.

The structures and spectral data thereof are shown in Tables 82 to 87.

TABLE 82 Ex. No Str. Chemical name P.D. 12-2

2-{(3S*,4R*)-3- [3-(4-fluoro- phenyl)ureido]- 4-(4-methoxy-phenyl)-2-oxo- pyrrolidin-1-yl} acetic acid ethyl ester ¹H-NMR (400 MHz,CDCl₃) δ 1.29 (3H, t, J = 7.4 Hz), 3.61 (1H, t, J = 9.2 Hz), 3.72 (1H,t, J = 9.2 Hz), 3.79 (3H, s), 3.81-3.89 (1H, m), 3.95 (1H, d, J = 17.8Hz), 4.17-4.25 (2H, m), 4.37 (1H, d, J = 17.8 Hz), 4.39-4.43 (1H, m),6.12 (1H, brs), 6.73 (2H, t, J = 8.6 Hz), 6.88 (2H, d, J = 8.6 Hz),7.05-7.09 (2H, m), 7.27 (2H, d, J = 8.6 Hz), 7.80 (1H, brs). MS (ESI⁺)m/z: 430 (MH⁺).

TABLE 83 Ex. No Str. Chemical name P.D. 12-3

2-{(3S*,4R*)-3- [3-(4-fluoro- phenyl)ureido]- 4-(4-methoxy-phenyl)-2-oxo- pyrrolidin-1-yl}- 2-methylpropionic acid ethyl ester¹H-NMR (400 MHz, CDCl₃) δ 1.18 (3H, t, J = 7.4 Hz), 1.52 (3H, s), 1.57(3H, s) 3.38 (1H, t, J = 9.2 Hz), 3.68 (1H, q, J = 9.2 Hz), 3.79 (3H,s), 3.83 (1H, t, J = 8.6 Hz), 4.10 (2H, q, J = 7.4 Hz), 4.80 (1H, dd, J= 11.6, 9.2 Hz), 5.87 (1H, brd, J = 8.6 Hz), 6.73 (2H, t, J = 9.2 Hz),6.89 (2H, d, J = 8.6 Hz), 7.10 (2H, dd, J = 9.2, 4.9 Hz), 7.30 (2H, d, J= 8.6 Hz), 7.88 (1H, brs). MS (ESI⁺) m/z: 458 (MH⁺). 12-4

(−)-1-(4-fluoro- phenyl)-3- [(3S*,4R*)-1-(1- hydroxy-2-methyl-propan-2-yl)- 4-(4-methoxy- phenyl)-2-oxo- pyrrolidin-3-yl] urea ¹H-NMR(400 MHz, CDCl₃) δ 1.39 (3H, s), 1.41 (3H, s), 3.42-3.53 (2H, m), 3.71(1H, q, J = 9.6 Hz), 3.80 (3H, s), 3.98-4.06 (2H, m), 4.17-4.24 (2H, m),6.49 (1H, brs), 6.70-6.75 (2H, m), 6.89 (2H, d, J = 8.6 Hz), 7.03-7.08(2H, m), 7.21 (2H, d, J = 8.6 Hz), 7.56 (1H, s). MS (ESI⁺) m/z: 416(MH⁺). [α] _(D) ²⁷ = −113 (c 0.31, EtOH).

TABLE 84 Ex. No Str. Chemical name P.D. 12-5

(−)-1-[4-(2,6- difluoro-4-methoxy- phenyl)-2-oxo pyrrolidin-3-yl]-3-(4-fluorophenyl) urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.13 (1H, d, J =10.4 Hz), 3.31 (3H, s), 3.72-3.76 (1H, m), 4.18-4.23 (1H, m), 4.61 (1H,dd, J = 9.8, 6.7 Hz), 6.04 (1H, d, J = 6.7 Hz), 6.66 (2H, d, J = 11.0Hz), 6.97-7.05 (2H, m), 7.22-7.26 (2H, m), 8.06 (1H, s), 8.65 (1H, s).MS (ESI⁺) m/z: 380 (MH⁺). [α] _(D) ²⁵ −239 (c 0.10, EtOH) 12-6

(+)-1-[4-(2,6- difluoro-4-methoxy- phenyl)-2-oxo pyrrolidin-3-yl]-3-(4-fluorophenyl) urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.13 (1H, d, J =10.4 Hz), 3.31 (3H, s), 3.72-3.76 (1H, m), 4.18-4.23 (1H, m), 4.61 (1H,dd, J = 9.8, 6.7 Hz), 6.04 (1H, d, J = 6.7 Hz), 6.66 (2H, d, J = 11.0Hz), 6.97-7.05 (2H, m), 7.22-7.26 (2H, m), 8.06 (1H, s), 8.65 (1H, s).MS (ESI⁺) m/z: 380 (MH⁺). [α] _(D) ²⁵ +188 (c 0.10, EtOH) 12-7

(−)-1-[4-(2,6- difluoro-4-methoxy- phenyl)-2-oxo pyrrolidin-3-yl]-3-(p-tolyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.17 (3H, s), 3.12 (1H, d, J= 10.4 Hz), 3.71 (3H, s), 3.72-3.76 (1H, m), 4.17-4.23 (1H, m), 4.61(1H, dd, J = 9.8, 6.7 Hz), 6.01 (1H, d, J = 6.7 Hz), 6.66 (2H, d, J =11.0 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz), 8.04 (1H,s), 8.49 (1H, s). MS (ESI⁺) m/z: 376 (MH⁺). [α] _(D) ²⁶ −142 (c 0.12,EtOH)

TABLE 85 Ex. No Str. Chemical name P.D. 12-8

(+)-1-[4-(2,6- difluoro-4-methoxy- phenyl)-2- oxopyrrolidin-3-yl]-3-(p-tolyl) urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.17 (3H, s), 3.12(1H, d, J = 10.4 Hz), 3.71 (3H, s), 3.72-3.76 (1H, m), 4.17-4.23 (1H,m), 4.61 (1H, dd, J = 9.8, 6.7 Hz), 6.01 (1H, d, J = 6.7 Hz), 6.66 (2H,d, J = 11.0 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz),8.04 (1H, s), 8.49 (1H, s). MS (ESI⁺) m/z: 376 (MH⁺). [α] _(D) ²⁶ +125(c 0.11, EtOH) 12-9

(−)-1-[4-(2,6- difluoro-4-methoxy- phenyl)-2- oxopyrrolidin-3-yl]-3-phenyl urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.13 (1H, d, J = 10.4Hz), 3.71 (3H, s), 3.74 (1H, dd, J = 10.4, 8.6 Hz), 4.21 (1H, t, J = 8.0Hz), 4.62 (1H, dd, J = 9.8, 6.7 Hz), 6.08 (1H, d, J = 6.7 Hz), 6.66 (2H,d, J = 13.8 Hz), 6.85 (1H, t, J = 7.4 Hz), 7.17 (2H, t, J = 7.3 Hz),7.23 (2H, t, J = 7.3 Hz), 8.06 (1H, s), 8.62 (1H, s). MS (ESI⁺) m/z: 362(MH⁺). [α] _(D) ²⁶ −201 (c 0.10, EtOH)

TABLE 86 Ex. No Str. Chemical name P.D. 12-10

(+)-1-[4-(2,6- difluoro-4-methoxy- phenyl)-2-oxo pyrrolidin-3-yl]-3-phenylurea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.13 (1H, d, J = 10.4 Hz), 3.71(3H, s), 3.74 (1H, dd, J = 10.4, 8.6 Hz), 4.21 (1H, t, J = 8.0 Hz), 4.62(1H, dd, J = 9.8, 7.3 Hz), 6.08 (1H, d, J = 7.3 Hz), 6.66 (2H, d, J =13.8 Hz), 6.85 (1H, t, J = 7.4 Hz), 7.17 (2H, t, J = 7.3 Hz), 7.23 (2H,t, J = 7.3 Hz), 8.05 (1H, s), 8.62 (1H, s). MS (ESI⁺) m/z: 362 (MH⁺).[α] _(D) ²⁶ +242 (c 0.10, EtOH) 12-11

(−)-1-(4-chloro phenyl)-3-[4-(4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.29 (1H, t, J = 7.4 Hz),3.67-3.72 (5H, m), 4.59 (1H, t, J = 6.7 Hz), 5.80 (1H, d, J = 6.7 Hz),6.85 (2H, d, J = 8.6 Hz), 7.05 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6 Hz), 8.10 (1H, s), 8.74 (1H, s). MS (ESI⁺)m/z: 360 (MH⁺). [α] _(D) ²⁵ −260 (c 0.10, EtOH) 12-12

(+)-1-(4-chloro phenyl)-3-[4-(4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.29 (1H, t, J = 7.4 Hz),3.67-3.72 (5H, m), 4.59 (1H, t, J = 6.7 Hz), 5.80 (1H, d, J = 6.7 Hz),6.85 (2H, d, J = 8.6 Hz), 7.05 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6 Hz), 8.10 (1H, s), 8.74 (1H, s). MS (ESI⁺)m/z: 360 (MH⁺). [α] _(D) ²⁵ +235 (c 0.10, EtOH)

TABLE 87 Ex. No Str. Chemical name P.D. 12-13

(+)-1-(4-fluoro phenyl)-3-[4-(4- methoxyphenyl)- 2-oxopyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.25-3.29 (1H, m), 3.68-3.72 (5H,m), 4.59 (1H, t, J = 6.7 Hz), 5.69 (1H, d, J = 6.7 Hz), 6.85 (2H, d, J =8.6 Hz), 7.00-7.06 (4H, m), 7.28-7.31 (2H, m), 8.09 (1H, s), 8.59 (1H,s). MS (ESI⁺) m/z: 344 (MH⁺). [α] _(D) ²⁵ +288 (c 0.10, EtOH) 12-14

(+)-1- [4-(4-methoxy- phenyl)-2-oxo- pyrrolidin-3-yl]-3- (p-tolyl)urea¹H-NMR (400 MHz, DMSO-d₆) δ 2.19 (3H, s), 3.26-3.29 (1H, m), 3.69-3.71(5H, m), 4.59 (1H, t, J = 6.7 Hz), 5.67 (1H, d, J = 6.7 Hz), 6.85 (2H,d, J = 8.6 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.17(2H, m), 8.08 (1H, s), 8.44 (1H, s). MS (ESI⁺) m/z: 340 (MH⁺). [α] _(D)²⁵ +177 (c 0.12, EtOH) 12-15

(+)-1-(4-fluoro phenyl)-3-[1-(2- hydroxyethyl)- 4-(4-methoxy-phenyl)-2-oxo- pyrrolidin-3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ3.29-3.39 (2H, m), 3.46 (1H, d, J = 9.8 Hz), 3.57 (2H, q, J = 5.5 Hz),3.66 (1H, t, J = 8.0 Hz), 3.69 (3H, s), 3.86 (1H, dd, J = 10.4, 6.7 Hz),4.69 (1H, t, J = 8.0 Hz), 4.86 (1H, brs), 5.76 (1H, brs), 6.84 (2H, d, J= 8.6 Hz), 7.00-7.06 (4H, m), 7.29 (2H, dd, J = 9.2, 5.5 Hz), 8.65 (1H,s). MS (ESI⁺) m/z: 388 (MH⁺). [α] _(D) ²⁵ +155 (c 0.11, EtOH)

Example 13-1

2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid ethyl ester

Trifluoroacetic acid (3 mL) was added to a solution of2-{(3S*,4R*)-3-[(tert-butoxycarbonyl)amino]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl]propionicacid ethyl ester (651 mg) in dichloromethane (12 mL) to produce areaction solution. The reaction solution was stirred at room temperaturefor 1 hour. The reaction solution was concentrated under reducedpressure, and ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the residue to adjust the pH of theaqueous layer to 9. 4-Fluorophenyl isocyanate (180 μL) was added to thesolution of two layers, and the mixture was stirred at room temperaturefor 15 minutes and extracted with ethyl acetate. The organic layer waswashed with water and a brine successively, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was then purified by silica gel column chromatography (ethylacetate:hexane=1:1 followed by 1:3), to obtain an isomer A (298 mg) as alow polar fraction and an isomer B (276 mg) as a high polar fractionthat were the title compounds as white solids.

Isomer A:

¹H-NMR (400 MHz, CDCl₃) δ 1.26 (3H, t, J=7.3 Hz), 1.48 (3H, d, J=7.4Hz), 3.35 (1H, t, J=11.0 Hz), 3.56-3.64 (1H, m), 3.75 (1H, d, J=9.2 Hz),3.79 (3H, s), 4.13-4.21 (2H, m), 4.84 (1H, q, J=7.4 Hz), 5.02 (1H, dd,J=11.6, 9.2 Hz), 5.65 (1H, d, J=9.2 Hz), 6.78 (2H, d, J=9.2 Hz), 6.88(2H, d, J=9.2 Hz), 7.14 (2H, dd, J=4.9, 9.2 Hz), 7.28 (2H, d, J=9.2 Hz),7.87 (1H, brs).

MS (ESI⁺) m/z: 444 (MH⁺).

[α]_(D) ²⁵=−102 (c 0.21, EtOH).

Isomer B:

¹H-NMR (400 MHz, CDCl₃) δ 1.28 (3H, t, J=6.7 Hz), 1.52 (3H, d, J=7.9Hz), 3.52 (1H, t, J=8.6 Hz), 3.80 (3H, s), 3.77-3.88 (2H, m), 4.16-4.22(3H, m), 4.90 (1H, q, J=7.9 Hz), 6.13 (1H, brd, J=6.7 Hz), 6.72-6.77(2H, m), 6.89 (2H, d, J=8.6 Hz), 7.04-7.08 (2H, m), 7.26 (2H, d, J=8.6Hz), 7.72 (1H, brs).

MS (ESI⁺) m/z: 444 (MH⁺).

[α]_(D) ²⁵=−94 (c 0.21, EtOH).

Example 14-1

(±)-trans-1-(4-Chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea

Trifluoroacetic acid (1.5 mL) and water (0.5 mL) were added to asolution of(±)-trans-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamicacid tert-butyl ester (1.2 g) in dichloromethane (2 mL) to produce areaction solution. The reaction solution was stirred at room temperaturefor 3 hours. The reaction solution was concentrated under reducedpressure, a saturated aqueous sodium hydrogen carbonate solution wasadded to the residue to adjust the pH of the aqueous layer to 9, and anethyl acetate-methanol (5:1) mixed liquid (10 mL) was added.4-Chlorophenyl isocyanate (396 mg) was added to the solution of twolayers, and the mixture was stirred at room temperature for 1 hour andextracted with ethyl acetate. The organic layer was washed with waterand a brine, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was then purified bysilica gel column chromatography (ethyl acetate followed by ethylacetate:methanol=4:1), to obtain the title compound as a white solid(500 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.13-3.20 (1H, m), 3.35-3.45 (3H, m), 3.52(2H, q, J=5.7 Hz), 3.61 (1H, t, J=6.7 Hz), 3.71 (3H, s), 4.57 (1H, t,J=10.0 Hz), 4.75 (1H, t, J=5.8 Hz), 6.52 (1H, d, J=9.1 Hz), 6.88 (2H, d,J=8.5 Hz), 7.23 (2H, d, J=9.1 Hz), 7.29 (2H, d, J=9.1 Hz), 7.38 (2H, d,J=8.5 Hz), 8.71 (1H, s).

MS (ESI⁺) m/z: 404 (MH⁺).

Example 15-1

(+)-trans-1-(4-Chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea(−)-trans-1-(4-Chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea

(+)-trans-1-(4-Chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea was subjected to opticalresolution by high performance liquid chromatography(hexane:ethanol=1:1, flow rate: 15.0 mL) using a column for separationof enantiomers (CHIRALPAK ID). An isomer A(−) with a retention time of7.91 minutes and an isomer B(+) with a retention time of 17.78 minutesthat were the title compounds were each obtained as a white solid.

Isomer A(−):

¹H-NMR (400 MHz, DMSO-d₆) δ 3.13-3.20 (1H, m), 3.35-3.45 (3H, m), 3.52(2H, q, J=5.7 Hz), 3.61 (1H, t, J=6.7 Hz), 3.71 (3H, s), 4.57 (1H, t,J=10.0 Hz), 4.75 (1H, t, J=5.8 Hz), 6.52 (1H, d, J=9.1 Hz), 6.88 (2H, d,J=8.5 Hz), 7.23 (2H, d, J=9.1 Hz), 7.29 (2H, d, J=9.1 Hz), 7.38 (2H, d,J=8.5 Hz), 8.71 (1H, s).

MS (ESI⁺) m/z: 404 (MH⁺).

[α]_(D) ²⁵=−140 (c 0.1, EtOH)

Isomer B(+):

¹H-NMR (400 MHz, DMSO-d₆) δ 3.13-3.20 (1H, m), 3.35-3.45 (3H, m), 3.52(2H, q, J=5.7 Hz), 3.61 (1H, t, J=6.7 Hz), 3.71 (3H, s), 4.57 (1H, t,J=10.0 Hz), 4.75 (1H, t, J=5.8 Hz), 6.52 (1H, d, J=9.1 Hz), 6.88 (2H, d,J=8.5 Hz), 7.23 (2H, d, J=9.1 Hz), 7.29 (2H, d, J=9.1 Hz), 7.38 (2H, d,J=8.5 Hz), 8.71 (1H, s).

MS (ESI⁺) m/z: 404 (MH⁺).

[α]_(D) ²⁶=+140 (c 0.1, EtOH)

Example 16-1

(−)-2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid

A 2 mol/L sodium hydroxide aqueous solution (0.6 mL) was added to asolution of2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid ethyl ester (258 mg) in methanol (3.0 mL) to produce a reactionsolution. The reaction solution was stirred at room temperature for 30minutes. A 1 mol/L hydrochloric acid was added to the reaction solutionto make the reaction solution acidic (pH: 1), and the mixture wasextracted with ethyl acetate. The organic layer was washed with a brine,and dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the crude product was washed with diisopropylether, to obtain the title compound as a white solid (228 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.34 (1H, t, J=9.8 Hz), 3.44-3.51 (1H, m),3.63 (1H, t, J=8.6 Hz), 3.71 (3H, s), 3.93 (1H, d, J=17.7 Hz), 4.05 (1H,d, J=17.7 Hz), 4.51-4.56 (1H, m), 6.56 (1H, d, J=9.2 Hz), 6.89 (2H, d,J=8.6 Hz), 7.03 (2H, t, J=8.6 Hz), 7.28 (2H, d, J=8.6 Hz), 7.33-7.37(2H, m), 8.58 (1H, s), 12.9 (1H, brs).

MS (ESI⁺) m/z: 402 (MH⁺).

[α]_(D) ²⁴=−90 (c 0.31, EtOH).

The same method as in Example 16-1 was performed using a correspondingester substance to obtain the following Examples 16-2 to 16-3. Thestructures and spectral data thereof are shown in Table 88.

TABLE 88 Ref. No Str. Chemical name P.D. 16-2

(−)-2-{(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy phenyl)-3-[3-(4-fluorophenyl) ureido]-2-oxo pyrrolidin-1-yl} acetic acid ¹H-NMR (400MHz, DMSO-d₆) δ 3.51-3.60 (2H, m), 3.72-3.82 (1H, m), 3.75 (3H, s), 3.87(1H, d, J = 17.0 Hz), 4.12 (1H, d, J = 17.0 Hz), 4.70 (1H, dd, J = 10.4,8.6 Hz), 6.61 (1H, brs), 6.71-6.6.78 (2H, m), 7.01 (2H, t, J = 9.2 Hz),7.33 (2H, dd, J = 9.2, 4.9 Hz), 8.68 (1H, s), 12.9 (1H, brs). MS (ESI⁺)m/z: 438 (MH⁺). [α] _(D) ²⁸ = −115 (c 0.08, EtOH) 16-3

(−)-2-{(3S*,4R*)- 4-(6-fluoro- 2,3-dihydro- benzofuran-5-yl)-3-[3-(4-fluoro- phenyl)ureido]- 2-oxopyrrolidin- 1-yl}acetic acid ¹H-NMR(400 MHz, DMSO-d₆) δ 3.12 (2H, t, J = 8.6 Hz), 3.40-3.52 (1H, m), 3.59(1H, t, J = 8.6 Hz), 3.66 (1H, t, J = 9.8 Hz), 3.90 (1H, d, J = 17.7Hz), 4.03 (1H, d, J = 17.7 Hz), 4.55 (2H, t, J = 8.6 Hz), 4.61-4.65 (1H,m), 6.60-6.70 (1H, m), 6.65 (1H, d, J = 11.0 Hz), 7.03 (2H, t, J = 8.6Hz), 7.32-7.37 (3H, m), 8.67 (1H, s), 12.99 (1H, brs). MS (ESI⁺) m/z:432 (MH⁺). [α] _(D) ²⁶ = −120 (c 0.13, DMSO)

Example 17-1

(−)-2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylacetamide

1-Hydroxybenzotriazole (46 mg), methylamine (0.5 mL, 2 mol/L,tetrahydrofuran solution), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (53 mg) were added to asolution of(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl)aceticacid (103 mg) in tetrahydrofuran (1.3 mL) under cooling to produce areaction solution. The reaction solution was stirred at room temperaturefor 3 hours. Water was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed with abrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, the residue was purified by preparative TLC(chloroform:methanol=9:1), and the crude product was washed withdiisopropyl ether, to obtain the title compound as a white solid (81mg).

¹H-NMR (400 MHz, CDCl₃) δ 2.83 (3H, d, J=4.9 Hz), 3.50 (1H, dd, J=9.8,6.7 Hz), 3.57 (1H, d, J=17.1 Hz), 3.77 (1H, t, J=7.4 Hz), 3.80 (3H, s),3.88-3.94 (1H, m), 4.00 (1H, t, J=9.8 Hz), 4.64 (1H, d, J=17.1 Hz), 6.67(2H, t, J=8.6 Hz), 6.89 (2H, d, J=8.6 Hz), 6.92-6.96 (2H, m), 7.04 (1H,d, J=6.7 Hz), 7.15 (2H, d, J=8.6 Hz), 7.80 (1H, brs), 7.87 (1H, d, J=4.9Hz).

MS (ESI⁺) m/z: 415 (MH⁺).

[α]_(D) ²⁵=−152 (c 0.31, EtOH).

The same method as in Example 17-1 was performed using a correspondingcarboxylic acid substance and amine to obtain the following Examples17-2 to 17-3. The structures and spectral data thereof are shown inTable 89.

TABLE 89 Ref. No Str. Chemical name P.D. 17-2

(−)-2-{(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy phenyl)-3-[3-(4-fluorophenyl) ureido]-2-oxo pyrrolidin-1-yl}- N-methyl- acetamide¹H-NMR (400 MHz, DMSO-d₆) δ 2.61 (3H, d, J = 4.9 Hz), 3.49-3.58 (2H, m),3.76 (3H, s), 3.82 (1H, q, J = 10.4 Hz), 3.88 (2H, s), 4.60 (1H, dd, J =10.4, 8.6 Hz), 6.68 (1H, brs), 6.71-6.79 (2H, m), 7.01 (2H, t, J = 9.2Hz), 7.33 (2H, dd, J = 9.2, 4.9 Hz), 7.92 (1H, q, J = 4.9 Hz), 8.85 (1H,s). MS (ESI⁺) m/z: 451 (MH⁺). [α] _(D) ²⁷ = −156 (c 0.11, EtOH) 17-3

(−)-2-{(3S*,4R*)- 4-(6-fluoro- 2,3-dihydro- benzofuran-5-yl)-3-[3-(4-fluoro- phenyl)ureido]- 2-oxopyrrolidin- 1-yl}acetamide ¹H-NMR(400 MHz, DMSO-d₆) δ 3.13 (2H, t, J = 8.6 Hz), 3.27-3.39 (1H, m), 3.56(1H, t, J = 8.6 Hz), 3.68-3.75 (1H, m), 3.78 (1H, d, J = 16.5 Hz), 3.86(1H, d, J = 16.5 Hz), 4.55 (2H, t, J = 8.6 Hz), 4.65 (1H, dd, J = 10.7,8.9 Hz), 6.59-6.64 (1H, m), 6.64 (1H, d, J = 11.0 Hz), 7.01-7.05 (2H,m), 7.19 (1H, s), 7.34-7.43 (4H, m), 8.77 (1H, s). MS (ESI⁺) m/z: 431(MH⁺). [α] _(D) ²⁷ = −145 (c 0.11, EtOH)

Example 18-1

(−)-2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid (isomer A)

The same method as in Example 16-1 was performed using(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid ethyl ester (isomer A) in place of2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid ethyl ester to obtain the title compound as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.35 (3H, d, J=7.4 Hz), 3.27-3.41 (2H, m),3.61 (1H, t, J=9.1 Hz), 3.71 (3H, s), 4.58 (1H, q, J=7.4 Hz), 4.66 (1H,dd, J=11.6, 9.2 Hz), 6.55 (1H, d, J=9.2 Hz), 6.88 (2H, d, J=8.6 Hz),7.03 (2H, t, J=8.6 Hz), 7.31-7.36 (4H, m), 8.46 (1H, s), 12.8 (1H, brs).

MS (ESI⁺) m/z: 416 (MH⁺).

[α]_(D) ²⁵=−103 (c 0.33, EtOH).

Example 19-1

(−)-2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl-2-oxopyrrolidin-1-yl}-N-methylpropionamide(isomer A)

The same method as in Example 17-1 was performed using(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid (isomer A) in place of(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl-2-oxopyrrolidin-1-yl}aceticacid to obtain the title compound as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.29 (3H, d, J=7.3 Hz), 2.62 (3H, d, J=4.9Hz), 3.28 (1H, t, J=9.8 Hz), 3.43-3.51 (1H, m), 3.68 (1H, t, J=8.6 Hz),3.71 (3H, s), 4.48-4.55 (2H, m), 6.54 (1H, d, J=9.2 Hz), 6.87 (2H, d,J=8.6 Hz), 7.04 (2H, t, J=8.6 Hz), 7.31-7.38 (4H, m), 7.83 (1H, d, J=4.9Hz), 8.67 (1H, brs).

MS (ESI⁺) m/z: 429 (MH⁺⁾.

[α]_(D) ²⁵=−199 (c 0.34, EtOH).

Example 20-1

(−)-2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid (isomer B)

The same method as in Example 16-1 was performed using(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid ethyl ester (isomer B) in place of2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid ethyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.36 (3H, d, J=7.4 Hz), 3.20 (1H, t, J=9.2Hz), 3.43-3.50 (1H, m), 3.68-3.74 (1H, m), 3.72 (3H, s), 4.49 (1H, dd,J=11.0, 8.6 Hz), 4.62 (1H, q, J=7.4 Hz), 6.53 (1H, d, J=8.6 Hz), 6.90(2H, d, J=8.6 Hz), 7.03 (2H, t, J=9.2 Hz), 7.27 (2H, d, J=8.6 Hz),7.32-7.38 (2H, m), 8.61 (1H, s), 12.9 (1H, brs).

MS (ESI⁺) m/z: 416 (MH⁺).

[α]_(D) ²⁵=−111 (c 0.32, EtOH).

Example 21-1

(−)-2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N-methylpropionamide(isomer B)

The same method as in Example 17-1 was performed using(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionic acid (isomerB) in place of(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.29 (3H, d, J=7.3 Hz), 2.57 (3H, d, J=4.9Hz), 3.24 (1H, t, J=9.8 Hz), 3.34-3.44 (1H, m), 3.66 (1H, t, J=8.6 Hz),3.72 (3H, s), 4.56 (1H, q, J=7.3 Hz), 4.69 (1H, dd, J=11.6, 9.2 Hz),6.50 (1H, d, J=9.2 Hz), 6.89 (2H, d, J=8.6 Hz), 7.03 (2H, t, J=9.2 Hz),7.30 (2H, d, J=8.6 Hz), 7.34-7.38 (2H, m), 7.87 (1H, d, J=4.9 Hz), 8.60(1H, s).

MS (ESI⁺) m/z: 429 (MH⁺).

[α]_(D) ²⁵=−94 (c 0.30, EtOH).

Example 22-1

2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionicacid

The same method as in Example 16-1 was performed using2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionicacid ethyl ester in place of2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid ethyl ester to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.52 (3H, s), 1.53 (3H, s), 3.36 (1H, t, J=9.2Hz), 3.60-3.80 (1H, m), 3.76 (3H, s), 3.78-3.86 (1H, m), 4.60-4.68 (1H,m), 6.06 (1H, brs), 6.72-6.78 (2H, m), 6.84 (2H, d, J=8.6 Hz), 7.07-7.13(2H, m), 7.23 (2H, d, J=8.6 Hz), 7.61 (1H, brs).

MS (ESI⁺) m/z: 430 (MH⁺).

Example 22-2

(−)-2-{(3S*,4R*)-4-(6-Fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-2-methylpropanoicacid

A 2 mol/L sodium hydroxide aqueous solution (0.2 mL) was added to asolution of2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-2-methylpropanoicacid ethylester (18 mg) in methanol (0.2 mL) to produce a reactionsolution. The reaction solution was stirred at room temperature for 18hours. A 1 mol/L hydrochloric acid was added to the reaction solution toadjust the pH of the reaction solution to 1, and the reaction solutionwas concentrated under reduced pressure. Water was added to theresulting residue, and the precipitate was collected by filtration andpurified by preparative TLC (chloroform:methanol=10:1) to obtain thetitle compound as a colorless solid (4.4 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 1.40 (3H, s), 1.42 (3H, s), 3.12 (2H, t,J=8.6 Hz), 3.28-3.37 (1H, m), 3.47-3.59 (1H, m), 3.70 (1H, t, J=8.3 Hz),4.53-4.62 (3H, m), 6.64 (1H, d, J=11.6 Hz), 6.70 (1H, brs), 7.02 (2H, t,J=8.9 Hz), 7.31-7.40 (3H, m), 8.73 (1H, brs), 12.47 (1H, brs).

MS (ESI⁺) m/z: 460 (MH⁺).

[α]_(D) ²⁷=−163 (c 0.09, DMSO)

Example 23-1

(−)-2-{(3S*,4R*)-3-[3-(4-Fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N,2-dimethylpropionamide

The same method as in Example 17-1 was performed using2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionicacid in place of(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.53 (3H, s), 1.72 (3H, s), 2.69 (3H, d, J=4.9Hz), 3.45-3.49 (1H, m), 3.80 (3H, s), 3.85 (2H, dd, J=7.3, 4.3 Hz),3.93-3.98 (1H, m), 6.73 (1H, brs), 6.78 (2H, t, J=9.2 Hz), 6.89 (2H, t,J=8.6 Hz), 7.08 (2H, dd, J=9.2, 4.9 Hz), 7.17 (2H, d, J=8.6 Hz), 7.36(1H, d, J=4.3 Hz), 7.88 (1H, brs).

MS (ESI⁺) m/z: 443 (MH⁺).

[α]_(D) ²⁹=−109 (c 0.31, EtOH).

Example 24-1

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-methy-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

10% Palladium on carbon (10 mg) was added to a solution of[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methy-2-oxopyrroidin-3-yl]carbamicacid benzyl ester (100 mg) in ethanol (5 mL) to produce a reactionsolution. The reaction solution was stirred under a hydrogen atmospherefor 1 hour. The reaction solution was filtered over Celite, and thesolvent was removed under reduced pressure to obtain(3S*,4R*)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-1-methylpyrrolidin-2-oneas a colorless oily intermediate compound. 4-Fluorophenyl isocyanate (28μL) was added to a solution of the resulting(3S*,4R*)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)-1-methylpyrrolidin-2-one(66 mg) in tetrahydrofuran (2.6 mL) to produce a reaction solution. Thereaction solution was stirred at room temperature for 20 minutes. Thereaction solution was concentrated under reduced pressure, and theresidue was then purified by silica gel column chromatography(hexane:ethyl acetate=4:1 followed by ethyl acetate), to obtain thetitle compound as a white solid (91 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.81 (3H, s), 3.40 (1H, dd, J=9.8, 9.2 Hz),3.53 (1H, t, J=9.2 Hz), 3.73-3.81 (1H, m), 3.75 (3H, s), 4.57 (1H, dd,J=9.8, 8.6 Hz), 6.52 (1H, d, J=8.6 Hz), 6.74 (2H, d, J=11.0 Hz),6.97-7.05 (2H, m), 7.30-7.36 (2H, m), 8.72 (1H, s).

MS (ESI⁺) m/z: 394 (MH⁺).

[α]_(D) ²⁷=−143 (c 0.10, EtOH)

The same method as in Example 24-1 was performed using a correspondingCbz substance and isocyanate to obtain the following Examples 24-2 to24-24.

The structures and spectral data thereof are shown in Tables 90 to 100.

TABLE 90 Ex. No Structure Chemical name P.D. 24-2

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxyphenyl)- 1-methyl-2-oxopyrrolidin-3- yl]-3-(p-tolyl) urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.18(3H, s), 2.81 (3H, s), 3.40 (1H, t, J = 9.2 Hz), 3.52 (1H, t, J = 7.8Hz), 3.71-3.80 (1H, m), 3.75 (3H, s), 4.56 (1H, dd, J = 10.4, 8.6 Hz),6.51 (1H, d, J = 8.6 Hz), 6.70-6.78 (2H, m), 6.98 (2H, d, J = 8.0 Hz),7.21 (2H, d, J = 8.0 Hz), 8.59 (1H, s). MS (ESI⁺) m/z: 390 (MH⁺). [α]_(D) ²⁷ = −120 (c 0.14, EtOH) 24-3

(−)-1-(4-cyano- phenyl)-3-[(3S*, 4R*)-4-(2,6-di- fluoro-4-methoxyphenyl)-1-methyl- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz, DMSO-d₆) δ2.81 (3H, s), 3.41 (1H, t, J = 9.8 Hz), 3.54 (1H, t, J = 9.8 Hz), 3.75(3H, s), 3.80 (1H, q, J = 9.8 Hz), 4.58 (1H, t, J = 9.8 Hz), 6.71-6.78(2H, m), 6.85 (1H, brd, J = 7.9 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.62 (2H,d, J = 8.0 Hz), 9.34 (1H, s). MS (ESI⁺) m/z: 401 (MH⁺). [α] _(D) ²⁷ =−176 (c 0.11, EtOH) 24-4

(−)-1-(6-chloro pyridin-3-yl)-3- [(3S*,4R*)-4-(2,6- difluoro-4-methoxyphenyl)-1- methyl-2-oxo- pyrrolidin-3-yl] urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.81 (3H, s), 3.41 (1H, t, J = 9.8 Hz), 3.53 (1H, t, J = 9.8Hz), 3.75 (3H, s), 3.80 (1H, q, J = 9.8 Hz), 4.57 (1H, t, J = 9.8 Hz),6.70-6.79 (2H, m), 6.94 (1H, brs), 7.32 (1H, d, J = 8.6 Hz), 7.87 (1H,dd, J = 8.6, 3.1 Hz), 8.35 (1H, d, J = 3.1 Hz), 9.24 (1H, brs). MS(ESI⁺) m/z: 411 (MH⁺). [α] _(D) ²⁷ = −197 (c 0.11, EtOH)

TABLE 91 Ex. No Structure Chemical name P.D. 24-5

(−)-1-(benzo[b] thiophen-2-yl)- 3-[(3S*,4R*)- 4-(2,6-difluoro-4-methoxy- phenyl)-1-methyl- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.83 (3H, s), 3.43 (1H, t, J = 9.8 Hz), 3.55 (1H, t, J = 9.8Hz), 3.75 (3H, s), 3.83 (1H, q, J = 9.8 Hz), 4.60 (1H, t, J = 9.8 Hz),6.67 (1H, s), 6.72-6.79 (2H, m), 6.84 (1H, brd, J = 8.0 Hz), 7.09 (1H,td, J = 7.9, 1.2 Hz), 7.21 (1H, td, J = 7.9, 1.2 Hz), 7.52 (1H, d, J =7.9 Hz), 7.69 (1H, d, J = 7.9 Hz), 10.1 (1H, s). MS (ESI⁺) m/z: 432(MH⁺). [α] _(D) ²⁹ = −189 (c 0.10, EtOH) 24-6

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy phenyl)-1-(2-hydroxyethyl)-2- oxopyrrolidin- 3-yl]-3-phenyl- urea ¹H-NMR (400 MHz,CDCl₃) δ 3.21-3.28 (1H, m), 3.35-3.44 (1H, m), 3.47-3.63 (4H, m),3.68-3.75 (1H, m), 3.75 (3H, s), 4.64-4.68 (1H, m), 4.77 (1H, t, J = 5.5Hz), 6.51 (1H, d, J = 8.6 Hz), 6.74 (2H, d, J = 10.4 Hz), 6.87 (1H, t, J= 7.3 Hz), 7.18 (2H, t, J = 7.9 Hz), 7.32 (2H, d, J = 7.3 Hz), 8.64 (1H,s). MS (ESI⁺) m/z: 406 (MH⁺). [α] _(D) ²⁴ = −88 (c 0.13, EtOH)

TABLE 92 Ex. No Structure Chemical name P.D. 24-7

(−)-1-[(3S*,4R*)- 4-(2,6-difluoro- 4-methoxy phenyl)-1-(2-hydroxyethyl)-2- oxopyrrolidin- 3-yl]-3-(p-tolyl) urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.18 (3H, s), 3.20-3.30 (1H, m), 3.33-3.43 (1H, m), 3.45-3.62(4H, m), 3.67-3.75 (1H, m), 3.75 (3H, s), 4.65 (1H, dd, J = 9.2, 8.6Hz), 4.77 (1H, t, J = 5.5 Hz), 6.46 (1H, d, J = 8.6 Hz), 6.70-6.77 (2H,m), 6.98 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz), 8.53 (1H, s). MS(ESI⁺) m/z: 420 (MH⁺). [α] _(D) ²⁷ = −199 (c 0.12, EtOH) 24-8

(−)-1-(4-cyano phenyl)-3-[(3S*, 4R*)-4-(2,6- difluoro-4-methoxy-phenyl)-1- (2-hydroxyethy1)- 2-oxopyrrolidin- 3-yl]urea ¹H-NMR(400 MHz, DMSO-d₆) δ 3.20-3.28 (1H, m), 3.37-3.46 (1H, m), 3.48-3.63(4H, m), 3.72-3.82 (1H, m), 3.75 (3H, s), 4.66 (1H, dd, J = 10.4, 8.6Hz), 4.78 (1H, t, J = 4.9 Hz), 6.70-6.78 (2H, m), 6.83 (1H, d, J = 8.6Hz), 7.49 (2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 8.6 Hz), 9.29 (1H, s).MS (ESI⁺) m/z: 431 (MH⁺). [α] _(D) ²⁸ = −148 (c 0.11, EtOH)

TABLE 93 Ex. No Structure Chemical name P.D. 24-9

(−)-1-(6- chloropyridin-3- yl)-3-[(3S*,4R*)- 4-(2,6-difluoro-4-methoxyphenyl)-1- (2-hydroxyethyl)- 2-oxopyrrolidin-3- yl]urea ¹H-NMR(400 MHz, DMSO-d₆) δ 3.18-3.28 (1H, m), 3.38-3.46 (1H, m), 3.47-3.63(4H, m), 3.73-3.81 (1H, m), 3.75 (3H, s), 4.66 (1H, dd, J = 11.0, 8.6Hz), 4.77 (1H, t, J = 5.5 Hz), 6.71-6.78 (2H, m), 6.83 (1H, d, J = 8.6Hz), 7.32 (1H, d, J = 8.6 Hz), 7.87 (1H, dd, J = 8.6, 3.0 Hz), 8.34 (1H,d, J = 3.0 Hz), 9.09 (1H, s). MS (ESI⁺) m/z: 441 (MH⁺). [α]_(D) ²⁶ =−153 (c 0.10, EtOH) 24-10

(−)-1- (benzo[b]thiophen- 2-yl)-3- [(3S*,4R*)-4-(2,6- difluoro-4-methoxyphenyl)-1- (2-hydroxyethyl)- 2-oxopyrrolidin-3- yl]urea ¹H-NMR(400 MHz, DMSO-d₆) δ 3.20-3.27 (1H, m), 3.40-3.48 (1H, m), 3.50-3.64(4H, m), 3.76 (3H, s), 3.80 (1H, q, J = 9.8 Hz), 4.68 (1H, dd, J = 9.8,8.6 Hz), 4.78 (1H, t, J = 5.5 Hz), 6.67 (1H, s), 6.72-6.79 (2H, m), 6.87(1H, brd, J = 8.0 Hz), 7.09 (1H, td, J = 7.9, 1.2 Hz), 7.21 (1H, td, J =7.9, 1.2 Hz), 7.52 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz), 10.1(1H, s). MS (ESI⁺) m/z: 462 (MH⁺). [α]_(D) ²⁸ = −170 (c 0.11, EtOH)

TABLE 94 Ex. No Structure Chemical name P.D. 24-11

(−)-1-[(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)-2- oxo-1-propylpyrrolidin-3- yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, CDCl₃)δ 0.96 (3H, t, J = 7.3 Hz), 1.57-1.67 (2H, m), 3.25-3.33 (1H, m),3.42-3.50 (1H, m), 3.57 (1H, t, J = 9.2 Hz), 3.62-3.70 (1H, m), 3.78(3H, s), 4.14-4.23 (1H, m), 4.39-4.46 (1H, m), 6.20 (1H, brs), 6.47 (2H,d, J = 10.4 Hz), 6.70-6.77 (2H, m), 7.03-7.10 (2H, m), 7.68 (1H, brs).MS (ESI⁺) m/z: 422 (MH⁺). [α]_(D) ²⁴ = −126 (c 0.19, EtOH) 24-12

(−)-1-[(3S*,4R*)-1- benzyl-4-(2,6- difluoro-4- methoxyphenyl)-2-oxopyrrolidin-3-yl]- 3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, CD₃CN) δ3.35-3.45 (2H, m), 3.72 (3H, s), 3.88 (1H, q, J = 9.2 Hz), 4.47 (2H, s),4.65 (1H, dd, J = 10.4, 8.0 Hz), 5.66 (1H, d, J = 8.0 Hz), 6.53 (2H, d,J = 11.0 Hz), 6.91 (2H, t, J = 9.2 Hz), 7.23-7.36 (7H, m), 7.48 (1H, s).MS (ESI⁺) m/z: 470 (MH⁺). [α]_(D) ²⁹ = −109 (c 0.17, EtOH) 24-13

(−)-1-[(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)-2- oxo-1-(pyridin-3-ylmethyl)pyrrolidin- 3-yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.46 (1H, t, J = 9.8 Hz), 3.55 (1H, t, J = 9.8 Hz), 3.74 (3H,s), 3.88 (1H, q, J = 9.6 Hz), 4.51 (1H, d, J = 15.9 Hz), 4.61-4.69 (2H,m), 6.64 (1H, d, J = 9.5 Hz), 6.74 (2H, d, J = 9.5 Hz), 7.03 (2H, td, J= 7.6, 2.2 Hz), 7.29-7.37 (4H, m), 7.81 (1H, td, J = 7.6, 1.8 Hz), 8.54(1H, q, J = 2.2 Hz), 8.74 (1H, s). MS (ESI⁺) m/z: 470 (MH⁺). [α]_(D) ³⁰= −142 (c 0.10, EtOH)

TABLE 95 Ex. No Structure Chemical name P.D. 24-14

(−)-1-{(3S*,4R*)-4-(2,6- difluoro-4- methoxyphenyl)-1-[(methylsulfonyl)methyl]- 2-oxopyrrolidin-3-yl}-3- (4-fluorophenyl)urea1H-NMR (400 MHz, DMSO-d₆) δ 3.31 (3H, s), 3.67 (1H, t, J = 9.5 Hz), 3.76(3H, s), 3.85 (1H, t, J = 8.9 Hz), 4.02 (1H, q, J = 9.8 Hz), 4.55 (1H,dd, J = 11.0, 7.9 Hz), 4.71 (1H, d, J = 14.7 Hz), 4.82 (1H, d, J = 14.7Hz), 6.72 (1H, d, J = 10.0 Hz), 6.77 (2H, d, J = 10.0 Hz), 7.03 (2H, dt,J = 14.5, 3.7 Hz), 7.33-7.36 (2H, m), 8.89 (1H, s). MS (ESI⁺) m/z: 472(MH⁺). [α]_(D) ²⁸ = −203 (c 0.10, EtOH) 24-15

(−)-{(3S*,4R*)-4-(2,6- difluoro-4- methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2- oxopyrrolidin-1- yl}methanesulfonamide ¹H-NMR(400 MHz, DMSO-d₆) δ 3.68-3.90 (6H, m), 4.53 (1H, d, J = 13.5 Hz), 4.69(1H, d, J = 13.5 Hz), 4.77 (1H, t, J = 10.0 Hz), 6.51 (1H, d, J = 8.6Hz), 6.76 (2H, d, J = 10.4 Hz), 7.03 (2H, t, J = 8.6 Hz), 7.09 (2H, s),7.31-7.35 (2H, m), 8.81 (1H, s). MS (ESI⁺) m/z: 473 (MH⁺). [α]_(D) ²⁵ =−120 (c 0.10, EtOH)

TABLE 96 Ex. No Structure Chemical name P.D. 24-16

(−)-2-{(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)-3- [3-(4-fluorophenyl)ureido]- 2-oxopyrrolidin-1- yl}acetic acid ethyl ester¹H-NMR (400 MHz, DMSO-d₆) δ 1.21 (3H, t, J = 6.7 Hz), 3.51-3.61 (2H, m),3.76 (3H, s), 3.82 (1H, q, J = 10.4 Hz), 3.97 (1H, d, J = 17.0 Hz), 4.13(2H, q, J = 6.7 Hz), 4.27 (1H, d, J = 17.0 Hz), 4.67 (1H, dd, J = 10.4,8.6 Hz), 6.68-6.80 (3H, m), 7.01 (2H, t, J = 9.2 Hz), 7.33 (2H, dd, J =9.2, 4.9 Hz), 8.79 (1H, s). MS (ESI⁺) m/z: 466 (MH⁺). [α]_(D) ²⁶ = −128(c 0.11, EtOH) 24-17

(−)-1-{(3S*,4R*)-4- (2,6-difluoro-4- methoxyphenyl)-1-[(5-methyloxazol-2- yl)methyl]-2- oxopyrrolidin-3-yl}- 3-(4-fluorophenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 2.27 (3H, s), 3.49 (1H, t,J = 9.2 Hz), 3.59 (1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.82 (1H, q, J =9.8 Hz), 4.44 (1H, d, J = 16.5 Hz), 4.64-4.71 (2H, m), 6.61 (1H, d, J =8.6 Hz), 6.75 (2H, d, J = 10.4 Hz), 6.80 (1H, s), 7.02 (2H, t, J = 9.2Hz), 7.33 (2H, dd, J = 8.6, 4.9 Hz), 8.71 (1H, s). MS (ESI⁺) m/z: 475(MH⁺). [α]_(D) ²⁵ = −108 (c 0.12, EtOH)

TABLE 97 Ex. No Structure Chemical name P.D. 24-18

(−)-1-{(3S*,4R*)- 4-(2,6-difluoro-4- methoxyphenyl)-1- [(5-methyl-1,3,4-oxadiazol-2- yl)methyl]-2- oxopyrrolidin-3- yl}-3-(4- fluorophenyl)urea¹H-NMR (400 MHz, DMSO-d₆) δ 2.49 (3H, s), 3.51 (1H, t, J = 9.2 Hz), 3.62(1H, t, J = 9.2 Hz), 3.75 (3H, s), 3.84 (1H, q, J = 9.2 Hz), 4.64-4.68(2H, m), 4.81 (1H, d, J = 16.5 Hz), 6.61 (1H, d, J = 8.6 Hz), 6.76 (2H,d, J = 11.0 Hz), 7.02 (2H, t, J = 9.2 Hz), 7.33 (2H, dd, J = 8.6, 4.9Hz), 8.71 (1H, s). MS (ESI⁺) m/z: 476 (MH⁺). [α]_(D) ²⁹ = −106 (c 0.11,EtOH) 24-19

(−)-1-[(3S*,4R*)- 4-(6-fluoro-2,3- dihydrobenzofuran- 5-yl)-1-(2-hydroxyethyl)-2- oxopyrrolidin-3- yl]-3-(4- fluorophenyl)urea ¹H-NMR(400 MHz, DMSO-d₆) δ 3.12 (2H, t, J = 8.6 Hz), 3.16-3.21 (1H, m),3.29-3.3.44 (2H, m), 3.49-3.53 (2H, m), 3.56-3.66 (2H, m), 4.55 (2H, t,J = 8.6 Hz), 4.62 (1H, t, J = 9.5 Hz), 4.76 (1H, t, 5.5 Hz), 6.53-6.66(1H, m), 6.64 (1H, d, J = 11.0 Hz), 7.03 (2H, t, J = 8.6 Hz), 7.34-7.39(3H, m), 8.67-8.76 (1H, m). MS (ESI⁺) m/z: 418 (MH⁺). [α]_(D) ²⁶ = −164(c 0.12, EtOH)

TABLE 98 Ex. No Structure Chemical name P.D. 24-20

(−)-2-{(3S*,4R*)-4- (6-fluoro-2,3- dihydrobenzofuran- 5-yl)-3-[3-(4-fluorophenyl)ureido]- 2-oxopyrrolidin-1- yl}acetic acid ethyl ester¹H-NMR (400 MHz, DMSO-d₆) δ 1.21 (3H, t, J = 6.7 Hz), 3.10-3.16 (2H, m),3.27-3.38 (1H, m), 3.60 (1H, t, J = 8.6 Hz), 3.65-3.70 (1H, m), 4.02(1H, d, J = 17.7 Hz), 4.11-4.19 (3H, m), 4.55 (2H, t, J = 8.3 Hz), 4.62(1H, t, J = 9.8 Hz), 6.66 (1H, d, J = 11.0 Hz), 6.81 (1H, brs), 7.03(2H, t, J = 8.6 Hz), 7.31-7.38 (3H, m), 8.81-8.84 (1H, m). MS (ESI⁺)m/z: 460 (MH⁺). [α]_(D) ²⁷ = −109 (c 0.11, EtOH) 24-21

(−)-2-{(3S*,4R*)-4- (6-fluoro-2,3- dihydrobenzofuran- 5-yl)-3-[3-(4-fluorophenyl)ureido]- 2-oxopyrrolidin-1- yl}-2- methylpropanoic acidethyl ester ¹H-NMR (400 MHz, DMSO-d₆) δ 1.18 (3H, t, J = 7.0 Hz), 1.39(3H, s), 1.44 (3H, s), 3.12 (2H, t, J = 8.9 Hz), 3.28-3.38 (1H, m), 3.60(1H, t, J = 10.1 Hz), 3.74 (1H, t, J = 8.9 Hz), 4.03-4.09 (2H, m),4.53-4.57 (3H, m), 6.62-6.67 (1H, m), 6.66 (1H, d, J = 11.0 Hz), 7.02(2H, t, J = 8.9 Hz), 7.33-7.36 (3H, m), 8.70 (1H, s). MS (ESI⁺) m/z: 488(MH⁺). [α]_(D) ²⁷ = −140 (c 0.12, EtOH)

TABLE 99 Ex. No Structure Chemical name P.D. 24-22

(−)-1-[(3S*,4R*)-1- (cyclopropylmethyl)- 4-(6-fluoro-2,3-dihydrobenzofuran- 5-yl)-2- oxopyrrolidin-3-yl]- 3-(4- fluorophenyl)urea¹H-NMR (400 MHz, DMSO-d₆) δ 0.21-0.29 (2H, m), 0.49-0.55 (2H, m),0.92-1.02 (1H, m), 3.03 (1H, dd, J = 13.9, 7.3), 3.17 (2H, t, J = 8.8Hz), 3.28 (1H, dd, J = 13.9, 7.0 Hz), 3.33-3.43 (1H, m), 3.64-3.73 (2H,m), 4.58-4.67 (1H, m), 4.60 (2H, t, J = 8.8 Hz), 6.64-6.71 (1H, m), 6.70(1H, J = 11.0 Hz), 7.07 (2H, t, J = 8.9 Hz), 7.38-7.46 (3H, m), 8.77(1H, s). MS (ESI⁺) m/z: 428 (MH⁺). [α]_(D) ²⁷ = −159 (c 0.11, EtOH)24-23

(−)-1-[(3S*,4R*)-1- (cyanomethyl)-4-(6- fluoro-2,3- dihydrobenzofuran-5-yl)-2- oxopyrrolidin-3-yl]- 3-(4- fluorophenyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.12 (2H, t, J = 9.1 Hz), 3.29-3.34 (1H, m), 3.65 (1H, t, J =9.1 Hz), 3.73-3.81 (1H, m), 4.44 (2H, s), 4.53-4.60 (3H, m), 6.65 (2H,d, J = 10.9 Hz), 7.25-7.32 (1H, m), 7.37-7.40 (3H, m), 9.32 (1H, brs).MS (ESI⁺) m/z: 413 (MH⁺). [α]_(D) ²⁶ = −136 (c 0.11, EtOH)

TABLE 100 Ex. No Structure Chemical name P.D. 24-24

(−)-1-{(3S*,4R*)-4- (6-fluoro-2,3- dihydrobenzofuran-5-yl)-1-[(5-methyl- 1,3,4-oxadiazol-2- yl)methyl]-2-oxopyrrolidin-3-yl}- 3-(4- fluorophenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ2.49 (3H, s), 3.12 (2H, t, J = 9.1 Hz), 3.29-3.37 (1H, m), 3.63 (1H, t,J = 9.1 Hz), 3.69-3.77 (1H, m), 4.55 (2H, t, J = 8.5 Hz), 4.62-4.76 (3H,m), 6.57 (1H, d, J = 9.1 Hz), 6.65 (1H, d, J = 10.9 Hz), 7.01-7.06 (2H,m), 7.34-7.38 (3H, m), 8.64 (1H, s). MS (ESI⁺) m/z: 470 (MH⁺). [α]_(D)²⁷ = −126 (c 0.10, EtOH)

Example 25-1

(−)-1-[(3S*,4R*)-4-(2-Fluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

The same method as in Example 24-1 was performed using[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester in place of[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.14-3.20 (1H, m), 3.28-3.42 (2H, m),3.48-3.52 (2H, m), 3.57-3.66 (2H, m), 3.72 (3H, s), 4.66 (1H, dd,J=11.0, 8.6 Hz), 4.73 (1H, t, J=5.5 Hz), 6.45 (1H, d, J=8.6 Hz),6.75-6.80 (2H, m), 6.98-7.04 (2H, m), 7.30-7.36 (2H, m), 7.44 (1H, dd,J=9.2, 9.2 Hz), 8.60 (1H, s).

MS (ESI⁺) m/z: 406 (MH⁺).

[α]_(D) ²⁷=−118 (c 0.10, EtOH)

Example 26-1

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

The same method as in Example 24-1 was performed using[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester in place of[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.21-3.30 (1H, m), 3.36-3.45 (1H, m),3.48-3.62 (4H, m), 3.71-3.78 (1H, m), 3.76 (3H, s), 4.66 (1H, dd,J=10.4, 8.6 Hz), 4.77 (1H, t, J=5.5 Hz), 6.51 (1H, d, J=8.6 Hz), 6.75(2H, d, J=11.0 Hz), 6.99-7.06 (2H, m), 7.31-7.37 (2H, m), 8.68 (1H, s).

MS (ESI⁺) m/z: 424 (MH⁺).

[α]_(D) ²⁷=−139 (c 0.11, EtOH)

Example 27-1

(+)-1-(4-Fluorophenyl)-3-[(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl-2-oxopyrrolidin-3-yl]urea

The same method as in Example 1-1 was performed using(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylicacid in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid toobtain the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.55 (1H, t, J=8.5 Hz), 3.74-3.82 (1H, m),3.80 (3H, s), 3.89 (3H, s), 4.01 (1H, t, J=8.2 Hz), 4.10 (1H, dd, J=8.5,8.2 Hz), 6.08 (1H, brs), 6.79 (2H, t, J=8.8 Hz), 6.89 (2H, d, J=9.1 Hz),7.12 (2H, q, J=4.6 Hz), 7.20 (2H, d, J=9.1 Hz), 7.50 (1H, brs).

MS (ESI⁺) m/z: 374 (MH⁺).

[α]_(D) ²⁷=+144 (c 0.12, EtOH)

Example 27-2

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-1-methoxy-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

The same method as in Example 1-1 was performed using(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methoxy-2-oxopyrrolidine-3-carboxylicacid in place of(−)-(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid toobtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.54-3.61 (1H, m), 3.73 (3H, s), 3.76 (3H,s), 3.80-3.89 (2H, m), 4.46 (1H, t, J=8.9 Hz), 6.67 (1H, d, J=8.6 Hz),6.77 (2H, d, J=8.6 Hz), 7.00-7.05 (2H, m), 7.32-7.36 (2H, m), 8.83 (1H,s).

MS (ESI⁺) m/z: 410 (MH⁺).

[α]_(D) ²⁵=−208 (c 0.20, EtOH)

Example 28-1

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

10% Palladium on carbon (49 mg) was added to a solution of1-[(3S*,4R*)-4-[4-(benzyloxy-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea(490 mg) in ethanol (10 mL) under an argon atmosphere to produce areaction solution. The reaction solution was stirred at room temperatureunder a hydrogen atmosphere for 4 hours. The reaction solution wasfiltered over Celite, and the solvent was removed under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1 followed by ethyl acetate), to obtain thetitle compound as a white solid (383 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.23-3.28 (1H, m), 3.41 (1H, t, J=9.2 Hz),3.74 (1H, q, J=9.6 Hz), 4.52 (1H, dd, J=10.7, 8.3 Hz), 6.41 (2H, d,J=10.4 Hz), 6.45 (1H, d, J=7.9 Hz), 6.99-7.04 (2H, m), 7.31-7.35 (2H,m), 8.01 (1H, s), 8.66 (1H, s).

MS (ESI⁺) m/z: 366 (MH⁺).

[α]_(D) ²⁸=−151 (c 0.1, EtOH)

Example 28-2

1-[(3S*,4R*)-4-(2,6-Difluoro-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea

The same method as in Example 28-1 was performed using1-[(3S*,4R*)-4-(4-(benzyloxy-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-phenylureain place of1-[(3S*,4R*)-4-(4-benzyloxy-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)ureato obtain the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 3.25-3.30 (1H, m), 3.42 (1H, t, J=8.6 Hz),3.74 (1H, q, J=9.6 Hz), 4.53 (1H, dd, J=11.0, 8.6 Hz), 6.41-6.47 (3H,m), 6.86 (1H, t, J=7.3 Hz), 7.18 (2H, t, J=7.9 Hz), 7.32 (2H, d, J=7.9Hz), 8.03 (1H, s), 8.60 (1H, s), 10.35 (1H, brs).

MS (ESI⁺) m/z: 348 (MH⁺).

Example 28-3

(−)-1-[(3S*,4R*)-4-(6-Fluoroindolin-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

The same method as in Example 28-1 was performed using1-[(3S*,4R*)-4-(1-benzyl-6-fluoroindolin-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)ureain place of1-[(3S*,4R*)-4-(4-benzyloxy-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)ureato obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.83 (2H, t, J=8.5 Hz), 3.11 (1H, t, J=9.7Hz), 3.35-3.44 (3H, m), 3.53-3.61 (1H, m), 4.47 (1H, dd, J=11.5, 9.1Hz), 5.68 (1H, br), 6.20 (1H, d, J=11.5 Hz), 6.36 (1H, d, J=8.5 Hz),7.00-7.05 (2H, m), 7.11 (1H, d, J=7.9 Hz), 7.33-7.37 (2H, m), 7.87 (1H,s), 8.55 (1H, s).

MS (ESI⁺) m/z: 373 (MH⁺).

[α]_(D) ²⁷=−202 (c 0.12, EtOH)

Example 28-4

(−)-1-[(3S*,4R*)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-ethynylphenyl)urea

Potassium carbonate (1 mg) was added to a solution of1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-{4-[(trimethylsilyl)ethynyl]phenyl}urea(66 mg) in methanol (1.4 mL) under ice-cooling to produce a reactionsolution. The reaction solution was stirred at room temperature for 8hours. The reaction solution was concentrated under reduced pressure,and the residue was then purified by silica gel column chromatography(hexane:ethyl acetate=1:1, ethyl acetate, and ethyl acetate:methanol=4:1in turn), to obtain the title compound as a colorless solid (44 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.27-3.32 (1H, m), 3.45 (1H, t, J=9.2 Hz),3.75 (3H, s), 3.80 (1H, ddd, J=11.0, 9.2, 9.2 Hz), 3.98 (1H, s), 4.56(1H, dd, J=11.0, 8.6 Hz), 6.57 (1H, d, J=8.6 Hz), 6.70-6.77 (2H, m),7.28 (2H, d, J=8.6 Hz), 7.35 (2H, d, J=8.6 Hz), 8.07 (1H, s), 8.89 (1H,s).

MS (ESI⁺) m/z: 386 (MH⁺).

[α]_(D) ²⁸=−147 (c 0.11, EtOH)

Example 28-5

(−)-1-{(3S*,4R*)-4-[2,6-Difluoro-4-(methylamino)phenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea

Trifluoroacetic acid (1 mL) was added to(3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}phenyl)(methyl)carbamicacid tert-butyl ester (80 mg) to produce a reaction solution. Thereaction solution was stirred at 60° C. for 1 hour. The reactionsolution was concentrated under reduced pressure, a saturated aqueoussodium hydrogen carbonate solution was added to the residue, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and a brine successively, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas then purified by silica gel column chromatography (ethyl acetate),to obtain the title compound as a colorless solid (30 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.63 (3H, d, J=4.9 Hz), 3.25 (1H, t, J=10.1Hz), 3.37 (1H, t, J=8.9 Hz), 3.67 (1H, q, J=9.8 Hz), 4.52 (1H, dd,J=11.0, 8.6 Hz), 6.16 (2H, d, J=12.0 Hz), 6.21 (1H, d, J=4.9 Hz), 6.40(1H, d, J=8.6 Hz), 6.99-7.04 (2H, m), 7.32-7.36 (2H, m), 7.98 (1H, s),8.61 (1H, s).

MS (ESI⁺) m/z: 379 (MH⁺).

[α]_(D) ²⁴=−54 (c 0.14, EtOH)

Example 28-6

1-[(3S,4R*)-4-(6-Fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

A Dess-Martin reagent (14 mg) was added to a solution of1-[(3S*,4R*)-4-(6-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea(13 mg) in a mixture of dichloromethane (0.66 mL) and acetonitrile (0.66mL) under an argon atmosphere under cooling to produce a reactionsolution. The reaction solution was stirred at room temperature for 3hours. A saturated aqueous sodium hydrogen carbonate solution was addedto the reaction solution, and the mixture was extracted with ethylacetate. The organic layer was washed with a brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=1:1, ethyl acetate, and ethylacetate:methanol=9:1 in turn), to obtain the title compound as acolorless solid (11 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.64-2.67 (2H, m), 3.15 (2H, t, J=5.2 Hz),3.27 (1H, t, J=8.6 Hz), 3.53 (1H, t, J=8.9 Hz), 3.89 (1H, q, J=9.8 Hz),4.65 (1H, dd, J=11.6, 8.6 Hz), 6.53 (1H, d, J=8.6 Hz), 7.00-7.04 (2H,m), 7.32-7.37 (3H, m), 7.82 (1H, d, J=6.1 Hz), 8.04 (1H, s), 8.69 (1H,s).

MS (ESI⁺) m/z: 386 (MH⁺).

Example 29-1

(−)-3,5-Difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}-N,N-dimethylbenzamide

Acetonitrile (3 mL), palladium(II) acetate (14 mg),(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (rac-BINAP) (38 mg),hexacarbonyl molybdenum (Mo(CO)₆) (240 mg), cesium carbonate (236 mg),and dimethylamine (3 mL, 2.0 M tetrahydrofran solution) were added to asolution of3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}phenyltrifluoromethanesulfonate (300 mg) in toluene (6 mL) to produce areaction solution. The reaction solution was stirred at 70° C. under anargon atmosphere for 3 hours. The reaction solution was filtered overCelite and washed with ethyl acetate. The solvent was removed underreduced pressure, and the residue was then purified by silica gel columnchromatography (hexane:ethyl acetate=4:1, ethyl acetate, and ethylacetate:methanol=9:1 in turn), to obtain the title compound as a whitesolid (192 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 2.88 (3H, s), 2.95 (3H, s), 3.35-3.39 (1H,m), 3.51 (1H, t, J=8.9 Hz), 3.94 (1H, q, J=9.6 Hz), 4.58 (1H, dd,J=10.7, 8.3 Hz), 6.50 (1H, d, J=7.9 Hz), 6.98-7.03 (2H, m), 7.17 (2H, d,J=9.2 Hz), 7.29-7.33 (2H, m), 8.11 (1H, s), 8.71 (1H, s).

MS (ESI⁺) m/z: 421 (MH⁺).

[α]_(D) ²⁸=−111 (c 0.1, EtOH)

Example 29-2

(−)-3,5-Difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}-N-methylbenzamide

The same method as in Example 29-1 was performed using methyl amine inplace of dimethyl amine to obtain the title compound.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.77 (3H, d, J=4.9 Hz), 3.34-3.40 (1H, m),3.51 (1H, t, J=9.2 Hz), 3.93 (1H, q, J=9.6 Hz), 4.60 (1H, dd, J=10.4,7.9 Hz), 6.53 (1H, d, J=7.9 Hz), 6.98-7.03 (2H, m), 7.29-7.32 (2H, m),7.52 (2H, d, J=9.8 Hz), 8.13 (1H, s), 8.56-8.60 (1H, m), 8.74 (1H, s).

MS (ESI⁺) m/z: 407 (MH⁺).

[α]_(D) ²⁸=−167 (c 0.1, EtOH)

Example 30-1

(−)-1-[(3S*,4R*)-4-(4-Cyano-2,6-difluorophenyl)2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea

Zinc cyanide (53 mg) and tetrakis(triphenylphosphine)palladium (18 mg)were added to a solution of3,5-difluoro-4-[(3R*,4S*)-4-(3-(4-fluorophenyl)ureido)-5-oxopyrrolidin-3-yl]phenyltrifluoromethanesulfonate (150 mg) in N,N-dimethylformamide (3 mL) underan argon atmosphere to produce a reaction solution. The reactionsolution was stirred at 80° C. for 5 hours. The reaction solution wasfiltered over Celite, the solvent was removed under reduced pressure,and the residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1 followed by ethyl acetate), to obtain thetitle compound as a white solid (100 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.33-3.38 (1H, m), 3.52 (1H, t, J=10.1 Hz),3.95 (1H, q, J=9.8 Hz), 4.58 (1H, dd, J=10.4, 7.3 Hz), 6.51 (1H, d,J=7.9 Hz), 6.98-7.04 (2H, m), 7.27-7.32 (2H, m), 7.81 (2H, d, J=8.6 Hz),8.18 (1H, s), 8.75 (1H, s).

MS (ESI⁺) m/z: 375 (MH⁺).

[α]_(D) ²⁸=−145 (c 0.1, EtOH)

Example 31-1

(−)-3,5-Difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}benzamide

A 2 mol/L sodium hydroxide aqueous solution (0.21 mL) was added to asolution of(−)-1-[(3S*,4R*)-4-(4-cyano-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea(160 mg) in methanol (4 mL) under an argon atmosphere to produce areaction solution. The reaction solution was stirred under heating atroom temperature for 1 hour. A 1 mol/L hydrochloric acid (1 mL) wasadded to the reaction solution to make the reaction solution acidic (pH:1), and the mixture was extracted with ethyl acetate. The organic layerwas washed with water and a brine, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas then purified by silica gel column chromatography (hexane:ethylacetate=4:1, ethyl acetate, and ethyl acetate:methanol=95:5 in turn), toobtain the title compound as a white solid (37 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.34-3.41 (1H, m), 3.52 (1H, t, J=9.2 Hz),3.94 (1H, q, J=9.6 Hz), 4.62 (1H, dd, J=10.7, 8.3 Hz), 6.52 (1H, d,J=7.9 Hz), 6.99-7.05 (2H, m), 7.30-7.34 (2H, m), 7.58 (2H, d, J=9.8 Hz),7.64 (1H, s), 8.10 (1H, s), 8.14 (1H, s), 8.74 (1H, s).

MS (ESI−) m/z: 391 (M-H)⁻.

HRESIMS (−): 391.10226 (calculated as C₁₈H₁₄F₃N₄O₃: 391.10180).

[α]_(D) ²⁸=−130 (c 0.1, EtOH)

Example 32-1

(−)-1-(4-Fluorophenyl)-3-[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea

10% Palladium on carbon (22 mg) was added to a solution of[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbamicacid benzyl ester (223 mg) in ethanol (12 mL) to produce a reactionsolution. The reaction solution was stirred under a hydrogen atmospherefor 1 hour. The reaction solution was filtered over Celite, and thefiltrate was removed under reduced pressure to obtain(3S*,4R*,Z)-3-amino-4-(4-methoxyphenyl)pyrrolidin-2-one O-methyloxime asa white solid. 4-Fluorophenyl isocyanate (68.3 μL) was added to asolution of the obtained(3S*,4R*,Z)-3-amino-4-(4-methoxyphenyl)pyrrolidin-2-one O-methyloxime(140 mg) in tetrahydrofuran (2 mL) to produce a reaction solution. Thereaction solution was stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure, and theresidue was then purified by silica gel column chromatography (ethylacetate:methanol=10:1), to obtain the title compound as a white solid(156 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.13 (1H, t, J=9.1 Hz), 3.22-3.30 (1H, m),3.48 (1H, t, J=8.2 Hz), 3.59 (3H, s), 3.70 (3H, s), 4.82 (1H, t, J=9.4Hz), 6.40 (1H, d, J=9.7 Hz), 6.69 (1H, s), 6.86 (2H, d, J=8.5 Hz),6.99-7.05 (2H, m), 7.26 (2H, d, J=8.5 Hz), 7.32-7.36 (2H, m), 8.45 (1H,s).

MS (ESI⁺) m/z: 373 (MH⁺).

[α]_(D) ²⁸=−72 (c 0.31, DMSO)

The same method as in Example 32-1 was performed using a correspondingimino substance and isocyanate to obtain the following Examples 32-2 to32-20.

The structures and spectral data thereof are shown in Tables 101 to 107.

TABLE 101 Ex. No Str. Chemical name P.D. 32-2

(−)-1-[(3S*,4R*, Z)-4-(2- fluoro-4-methoxyphenyl)- 2-(methoxyimino)pyrrolidin- 3-yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.08-3.15 (1H, m), 3.40-3.49 (2H, m), 3.58 (3H, s), 3.71 (3H,s), 4.97 (1H, t, J = 9.2 Hz), 6.39 (1H, d, J = 9.2 Hz), 6.71-6.77 (3H,m), 6.97-7.03 (2H, m), 7.29-7.34 (2H, m), 7.38 (1H, dd, J = 8.6, 8.6Hz), 8.48 (1H, s). MS (ESI⁺) m/z: 391 (MH⁺). [α]_(D) ²⁹ = −50 (c 0.10,EtOH) 32-3

(−)-1-[(3S*,4R*,Z)-4-(2,6- difluoro-4- methoxyphenyl)-2-(methoxyimino)pyrrolidin- 3-yl]-3-(4- fluorophenyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.26-3.46 (2H, m), 3.53-3.59 (1H, m), 3.60 (3H, s), 3.74 (3H,s), 5.08 (1H, t, J = 9.2 Hz), 6.43 (1H, d, J = 9.2 Hz), 6.71 (2H, d, J =11.0 Hz), 6.80 (1H, s), 6.98-7.03 (2H, m), 7.29-7.33 (2H, m), 8.56 (1H,s). MS (ESI⁺) m/z: 409 (MH⁺). [α]_(D) ²⁷ = −67 (c 0.10, EtOH) 32-4

(−)-1-(4-fluorophenyl)-3- {(3S*,4R*,Z)-2-[(2- hydroxyethoxy)imino]-4-(4- methoxyphenyl)pyrrolidin- 3-yl}urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.15(1H, t, J = 9.1 Hz), 3.22-3.30 (1H, m), 3.48-3.58 (3H, m), 3.70 (3H, s),3.80 (2H, t, J = 5.4 Hz), 4.45 (1H, t, J = 5.8 Hz), 4.82 (1H, t, J = 9.4Hz), 6.39 (1H, d, J = 8.5 Hz), 6.69 (1H, s), 6.86 (2H, d, J = 9.1 Hz),6.99-7.05 (2H, m), 7.27 (2H, d, J = 9.1 Hz), 7.31-7.36 (2H, m), 8.45(1H, s). MS (ESI⁺) m/z: 403 (MH⁺). [α]_(D) ²⁸ = −86 (c 0.36, EtOH)

TABLE 102 Ex. No Str. Chemical name P.D. 32-5

(−)-1-{(3S*,4R*,Z)-4-(2,6- difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)- imino]pyrrolidin- 3-yl}-3-(4-fluorophenyl)urea¹H-NMR (400 MHz, DMSO-d₆) δ 3.27-3.31 (1H, m), 3.45 (1H, t, J = 9.8 Hz),3.50-3.62 (3H, m), 3.74 (3H, s), 3.80-3.82 (2H, m), 4.47 (1H, t, J = 5.5Hz), 5.07 (1H, dd, J = 10.4, 9.2 Hz), 6.42 (1H, d, J = 9.2 Hz), 6.71(2H, d, J = 11.0 Hz), 6.79 (1H, s), 6.97-7.04 (2H, m), 7.26-7.34 (2H,m), 8.56 (1H, s). MS (ESI⁺) m/z: 439 (MH⁺). [α]_(D) ²⁷ = −105 (c 0.10,EtOH) 32-6

1-[(3S*,4R*,Z)-4-(2,6- difluoro-4-methoxyphenyl)-2-(methylimino)pyrrolidin-3-yl] -3-(4-fluorophenyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.68 (3H, d, J = 4.3 Hz), 3.35-3.51 (2H, m), 3.66-3.80 (4H,m), 5.04 (1H, t, J = 8.6 Hz), 5.96-6.03 (1H, m), 6.59 (1H, d, J = 9.8Hz), 6.71 (2H, d, J = 10.4 Hz), 7.02 (2H, t, J = 9.2 Hz), 7.32-7.39 (2H,m), 8.53 (1H, s). MS (ESI⁺) m/z: 393 (MH⁺). [α]_(D) ²⁸ = −205 (c 0.10,EtOH). 32-7

(+)-1-(4-fluorophenyl)-3- [(3R*,4S*,Z)-2-(methoxy-imino)-4-(4-methoxyphenyl) pyrrolidin-3-yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.13 (1H, t, J = 9.1 Hz), 3.22-3.30 (1H, m), 3.48 (1H, t, J =8.2 Hz), 3.59 (3H, s), 3.70 (3H, s), 4.82 (1H, t, J = 9.4 Hz), 6.40 (1H,d, J = 9.7 Hz), 6.69 (1H, s), 6.86 (2H, d, J = 8.5 Hz), 6.99-7.05 (2H,m), 7.26 (2H, d, J = 8.5 Hz), 7.32-7.36 (2H, m), 8.45 (1H, s). MS (ESI⁺)m/z: 373 (MH⁺). [α]_(D) ²⁷ = +100 (c 0.15, EtOH)

TABLE 103 Ex. No Structure Chemical name P.D. 32-8

(−)-1-[(3S*,4R*,Z)-4-(2,6- difluoro-4- methoxyphenyl)-2-(methoxyimino)pyrrolidin- 3-yl]-3-(p-tolyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.18 (3H, s), 3.25-3.31 (1H, m), 3.43 (1H, t, J = 9.2 Hz),3.53 (1H, q, J = 9.2 Hz), 3.60 (3H, s), 3.74 (3H, s), 5.07 (1H, dd, J =9.2, 8.6 Hz), 6.38 (1H, d, J = 8.6 Hz), 6.67-6.74 (2H, m), 6.79 (1H, s),6.97 (2H, d, J = 8.6 Hz), 7.18 (2H, d, J = 8.6 Hz), 8.40 (1H, s). MS(ESI⁺) m/z: 405 (MH⁺). [α]_(D) ²⁷ = −102 (c 0.11, EtOH) 32-9

(−)-1-(4-cyanophenyl)-3- [(3S*,4R*,Z)-4-(2,6- difluoro-4-methoxyphenyl)-2- (methoxyimino)pyrrolidin- 3-yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.25-3.34 (1H, m), 3.44 (1H, t, J = 9.2 Hz), 3.56-3.65 (1H,m), 3.60 (3H, s), 3.74 (3H, s), 5.08 (1H, dd, J = 10.4, 8.6 Hz),6.68-6.76 (2H, m), 6.77-6.84 (2H, m), 7.49 (2H, d, J = 8.6 Hz), 7.62(2H, d, J = 8.6 Hz), 9.18 (1H, s). MS (ESI⁺) m/z: 416 (MH⁺). [α]_(D) ²⁸= −69 (c 0.10, EtOH) 32-10

(−)-1-(6-chloropyridin-3- yl)-3-[(3S*,4R*,Z)-4-(2,6- difluoro-4-methoxyphenyl)-2- (methoxyimino)pyrrolidin- 3-yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.25-3.35 (1H, m), 3.43 (1H, t, J = 8.6 Hz), 3.58-3.66 (1H,m), 3.60 (3H, s), 3.74 (3H, s), 5.08 (1H, dd, J = 10.4, 8.6 Hz),6.68-6.80 (3H, m), 6.81 (1H, s), 7.31 (1H, d, J = 8.6 Hz), 7.85 (1H, dd,J = 8.6, 3.0 Hz), 8.32 (1H, d, J = 3.0 Hz), 8.94 (1H, s). MS (ESI⁺) m/z:426 (MH⁺). [α]_(D) ²⁶ = −66 (c 0.13, EtOH)

TABLE 104 Ex. No Structure Chemical name P.D. 32-11

(−)-1-(benzo[b]thiophen-2-yl)-3- [(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2- (methoxyimino)pyrrolidin-3- yl]urea ¹H-NMR (400 MHz,DMSO-d₆) δ 3.27-3.33 (1H, m), 3.60 (3H, s), 3.44 (1H, t, J = 9.2 Hz),3.62-3.71 (1H, m), 3.74 (3H, s), 5.09 (1H, dd, J = 9.8, 9.2 Hz), 6.66(1H, s), 6.70-6.76 (2H, m), 6.81-6.87 (2H, m), 7.08 (1H, td, J = 7.9,1.2 Hz), 7.20 (1H, td, J = 7.9, 1.2 Hz), 7.51 (1H, d, J = 7.9 Hz), 7.69(1H, d, J = 7.9 Hz), 9.93 (1H, s). MS (ESI⁺) m/z: 447 (MH⁺). [α]_(D) ²⁸= 78 (c 0.10, EtOH) 32-12

(−)-1-{(3S*,4R*,Z)-4-(2,6- difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin- 3-yl}-3-(p-tolyl)urea ¹H-NMR (400 MHz,DMSO-d₆) δ 2.18 (3H, s), 3.27-3.34 (1H, m), 3.45 (1H, t, J = 8.6 Hz),3.50-3.60 (3H, m), 3.74 (3H, s), 3.79-3.82 (2H, m), 4.47 (1H, t, J = 6.1Hz), 5.07 (1H, dd, J = 10.6, 8.6 Hz), 6.35 (1H, d, J = 8.6 Hz),6.67-6.75 (2H, m), 6.78 (1H, s), 6.97 (2H, d, J = 8.6 Hz), 7.17 (2H, d,J = 8.6 Hz), 8.40 (1H, s). MS (ESI⁺) m/z: 435 (MH⁺). [α]_(D) ²⁸ = −52 (c0.17, EtOH) 32-13

(−)-1-(4-cyanophenyl)-3- {(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2- hydroxyethoxy)imino]pyrrolidin- 3-yl}urea ¹H-NMR(400 MHz, DMSO-d₆) δ 3.28-3.34 (1H, m), 3.46 (1H, t, J = 8.6 Hz),3.51-3.67 (3H, m), 3.74 (3H, s), 3.79-3.82 (2H, m), 4.47 (1H, t, J = 5.5Hz), 5.07 (1H, dd, J = 10.6, 8.6 Hz), 6.68-6.77 (3H, m), 6.82 (1H, s),7.48 (2H, d, J = 9.2 Hz), 7.62 (2H, d, J = 9.2 Hz), 9.14 (1H, s). MS(ESI⁺) m/z: 446 (MH⁺). [α]_(D) ²⁵ = −88 (c 0.10, EtOH)

TABLE 105 Ex. No Structure Chemical name P.D. 32-14

(−)-1-(6-chloropyridin- 3-yl)-3-{(3S*,4R*,Z)-4- (2,6-difluoro-4-methoxyphenyl)-2-[(2- hydroxyethoxy)imino]- pyrrolidin-3-yl}urea ¹H-NMR(400 MHz, DMSO-d₆) δ 3.27-3.32 (1H, m), 3.46 (1H, t, J = 8.6 Hz),3.52-3.67 (3H, m), 3.74 (3H, s), 3.81 (2H, t, J = 5.5 Hz) 4.45 (1H, t, J= 5.5 Hz), 5.07 (1H, dd, J = 10.4, 8.6 Hz), 6.68-6.76 (2H, m), 6.78-6.83(2H, m), 7.31 (1H, d, J = 8.6 Hz), 7.84 (1H, dd, J = 8.6, 3.0 Hz), 8.32(1H, d, J = 3.0 Hz), 9.00 (1H, s). MS (ESI⁺) m/z: 456 (MH⁺). [α]_(D) ²⁷= −71 (c 0.10, EtOH) 32-15

(−)-1-(benzo[b]thiophen- 2-yl)-3-{(3S*,4R*,Z)-4- (2,6-difluoro-4-methoxyphenyl)-2-[(2- hydroxyethoxy)imino]- pyrrolidin-3-yl}urea ¹H-NMR(400 MHz, DMSO-d₆) δ 3.27-3.35 (1H, m), 3.55 (1H, t, J = 9.8 Hz),3.52-3.60 (2H, m), 3.67 (1H, q, J = 9.8 Hz), 3.74 (3H, s), 3.81 (2H, t,J = 4.9 Hz), 4.46 (1H, t, J = 5.5 Hz), 5.09 (1H, dd, J = 10.4, 9.2 Hz),6.66 (1H, s), 6.70-6.77 (2H, m), 6.80 (1H, brd, J = 9.2 Hz), 6.821 (1H,s), 7.08 (1H, td, J = 7.9, 1.2 Hz), 7.20 (1H, td, J = 7.9, 1.2 Hz), 7.51(1H, d, J = 7.9 Hz), 7.68 (1H, d, J = 7.9 Hz), 9.89 (1H, s). MS (ESI⁺)m/z: 477 (MH⁺). [α]_(D) ²⁹ −91 (c 0.12, EtOH) 32-16

(−)-1-{(3R*,4S*)-3-(2,6- difluoro-4-methoxy- phenyl)-5-[(1-methyl-1H-pyrazol-3- yl)amino]-3,4-dihydro- 2H-pyrrol-4-yl}-3-(4-fluorophenyl)urea ¹H-NMR (400 MHz, DMSO-d₆) δ 3.50-3.73 (3H, m), 3.76(3H, s), 3.76 (3H, s), 5.04 (1H, t, J = 8.9 Hz), 5.85 (1H, d, J = 2.4Hz), 6.43 (1H, d, J = 7.9 Hz), 6.73 (2H, d, J = 11.0 Hz), 6.98-7.04 (2H,m), 7.30-7.36 (2H, m), 7.50 (1H, d, J = 2.4 Hz), 8.41 (1H, s), 8.72 (1H,s). MS (ESI⁺) m/z: 459 (MH⁺). [α]_(D) ²⁴ = −30 (c 0.16, EtOH)

TABLE 106 Ex. No Structure Chemical name P.D. 32-17

(−)-1-[(3S*,4R*,Z)-4-(2,6- difluoro-4-methoxyphenyl)-2-(morpholinoimino)pyrrolidin-3- yl]-3-(4-fluorophenyl)urea ¹H-NMR (400MHz, CDCl₃) δ 2.74-2.84 (4H, m), 3.57-3.83 (10H, m), 5.46 (1H, brs),5.95 (1H, brs), 6.46 (2H, d, J = 11.0 Hz), 6.75-6.82 (2H, m), 7.06-7.12(2H, m), 9.11 (1H, brs). MS (ESI⁺) m/z: 464 (MH⁺). [α]_(D) ²⁴ = −31 (c0.14, EtOH) 32-18

1-[(3R*,4S*)-3-(2,6-difluoro-4- methoxyphenyl)-5-(phenylamino)-3,4-dihydro-2H- pyrrol-4-yl]-3-(4- fluorophenyl)urea¹H-NMR (400 MHz, DMSO-d₆) δ 3.52-3.63 (2H, m), 3.75 (3H, s), 3.99-4.08(1H, m), 5.16 (1H, t, J = 8.9 Hz), 6.72 (2H, d, J = 11.0 Hz), 6.75 (1H,d, J = 6.4 Hz), 6.88 (1H, t, J = 7.9 Hz), 7.00-7.05 (2H, m), 7.22 (2H,t, J = 7.9 Hz), 7.36-7.40 (2H, m), 7.83 (2H, d, J = 7.9 Hz), 8.56 (1H,s), 8.60 (1H, s). MS (ESI⁺) m/z: 455 (MH⁺). 32-19

(−)-1-((3S*,4R*,Z)-4-(6-fluoro- 2,3-dihydrobenzofuran-5-yl)-2- [(2-hydroxyethoxy)imino]pyrrolidin- 3-yl)-3-(4-fluorophenyl)urea ¹H-NMR (400MHz, DMSO-d₆) δ 3.08-3.17 (3H, m), 3.42-3.49 (2H, m), 3.54-3.56 (2H, m),3.79-3.81 (2H, m), 4.47 (1H, t, J = 5.2 Hz), 4.54 (2H, t, J = 8.6 Hz),4.95 (1H, t, J = 8.9 Hz), 6.60-6.70 (3H, m), 7.02 (2H, t, J = 8.9 Hz),7.30-7.36 (3H, m), 8.73 (1H, s). MS (ESI⁺) m/z: 433 (MH⁺). [α]_(D) ²⁵ =−137 (c 0.14, EtOH)

TABLE 107 Ex. No Structure Chemical name P.D. 32-20

3-((Z)-{(3S,4R)-4-(2,6- difluoro-4-methoxyphenyl)-3- [3-(4-fluorophenyl)ureido]pyrrolidin- 2-ylidenelamino)propanoic acid ethylester ¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J = 7.3 Hz), 2.65 (2H, t, J = 7.3Hz), 3.42-3.53 (2H, m), 3.57-3.66 (1H, m), 3.75 (3H, s), 3.86-3.93 (1H,m), 3.97-4.10 (3H, m), 5.18 (1H, t, J = 8.6 Hz), 6.70 (1H, d, J = 8.6Hz), 6.77 (2H, d, J = 11.0 Hz), 7.04 (2H, t, J = 8.6 Hz), 7.33-7.37 (2H,m), 8.99 (1H, s). MS (ESI⁺) m/z: 479 (MH⁺).

Example 33-1

(−)-1-(4-Fluorophenyl)-3-[(3S*,4R*,Z)-2-(2-hydroxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea

Water (1.35 mL) and trifluoroacetic acid (135 μL) were added to asolution of1-((3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea (290 mg) in1,4-dioxane (1.5 mL) to produce a reaction solution. The reactionsolution was stirred at room temperature for 30 minutes. After that, asaturated aqueous sodium hydrogen carbonate solution was added to thereaction solution under ice-cooling, and the mixture was extracted withethyl acetate. The organic layer was washed with a brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was washed with diisopropyl ether, to obtainthe title compound as a white solid (212 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.19 (1H, t, J=9.1 Hz), 3.30 (1H, q, J=8.7Hz), 3.55 (1H, t, J=8.2 Hz), 3.76 (3H, s), 4.80 (1H, t, J=9.4 Hz), 6.37(1H, d, J=9.1 Hz), 6.43 (1H, s), 6.92 (2H, d, J=8.5 Hz), 7.04-7.10 (2H,m), 7.32 (2H, d, J=8.5 Hz), 7.36-7.40 (2H, m), 8.49 (1H, s), 8.89 (1H,s).

MS (ESI⁺) m/z: 359 (MH⁺).

[α]_(D) ²⁹=−95 (c 0.30, EtOH)

Example 33-2

(−)-1-((3S*,4R*,Z)-4-(2,6-Difluoro-4-methoxyphenyl)-2-(hydroxyimino)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea

The same method as in Example 33-1 was performed using1-((3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl oxy]imino}-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea in placeof 1-((3S*,4R*,Z)-2-{[(tert-butyldimethylsilyl)oxy]imino}-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea to obtain the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.26-3.33 (1H, m), 3.42 (1H, t, J=8.6 Hz),3.49-3.57 (1H, m), 3.75 (3H, s), 5.02 (1H, t, J=9.8 Hz), 6.33 (1H, d,J=8.6 Hz), 6.48 (1H, s), 6.72 (2H, d, J=10.4 Hz), 6.97-7.04 (2H, m),7.26-7.32 (2H, m), 8.52 (1H, s), 8.90 (1H, s).

MS (ESI⁺) m/z: 395 (MH⁺).

[α]_(D) ²⁶=−21 (c 0.10, EtOH)

Example 34-1

(−)-1-{(3S*,4R*)-1-[(2H-Tetrazol-5-yl)methyl]-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea

Sodium azide (22 mg), triethylamine (47 μL), and acetic acid (19 μL)were added to a solution of1-[(3S*,4R*)-1-(cyanomethyl)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea(35 mg) in a mixture of toluene (850 μL) and N,N-dimethylformamide (500μL) to produce a reaction solution. The reaction solution was stirred at125° C. for 2 hours. The reaction solution was allowed to cool to roomtemperature, a 10% citric acid aqueous solution was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and a brine successively, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and theresulting crude product was washed with diethyl ether, to obtain thetitle compound as a pale brown solid (24 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ 3.12 (2H, t, J=8.6 Hz), 3.31-3.35 (1H, m),3.64 (1H, t, J=9.2 Hz), 3.71-3.78 (1H, m), 4.55 (2H, t, J=9.2 Hz),4.70-4.76 (2H, m), 4.85-4.89 (1H, m), 6.51 (1H, d, J=9.2 Hz), 6.64 (1H,d, J=11.0 Hz), 7.01-7.06 (2H, m), 7.34-7.40 (3H, m), 8.67 (1H, s), 16.47(1H, brs).

MS (ESI⁺) m/z: 456 (MH⁺).

[α]_(D) ²⁶=−120 (c 0.09, EtOH)

Next, results in support of availability of the compound of the presentinvention will be shown with reference to Test Examples.

Test Example 1 Measurement Test of Agonist Activity on Human FPRL1 (1-1)Construction of Human FPRL1 Expression Vector

Human FPRL (SEQ ID NO: 3) was amplified in a PCR reaction from cDNAderived from a monocytic leukemia cell line THP-1 (TIB-202, ATCC) as atemplate using a forward primer shown in SEQ ID NO: 1, a reverse primershown in SEQ ID NO: 2, and KOD-plus-ver. 2 (KOD-211, TOYOBO CO., LTD.).The amplified PCR product and pCMV-script vector (212220, STRATAGENE)were digested with Hind III (1060A, Takara Bio Inc.) and XhoI (1094A,Takara Bio Inc.), and the resultant digest was ligated with Ligationhigh ver. 2 (LGK-201, TOYOBO CO., LTD.). The ligation product wastransformed into DH5α (DNA-901, TOYOBO CO., LTD.), cultured on a 100μg/mL kanamycin-containing LB medium, and purified with HiSpeed PlasmidMaxi Kit (12662, QIAGEN).

(1-2) Construction of human Gα15 expression vector Human Gα15 (SEQ IDNO: 6) was amplified in a PCR reaction from cDNA derived from a myeloidleukemia cell line HL-60 (CCL-240, ATCC) as a template using a forwardprimer shown in SEQ ID NO: 4, a reverse primer shown in SEQ ID NO: 5,and KOD-plus-ver. 2. The amplified PCR product and pCMV-script vectorwere digested with Hind III and XhoI, and the resultant digest wasligated with Ligation high ver. 2. The ligation product was transformedinto DH5α, cultured on a 100 μg/mL kanamycin-containing LB medium, andpurified with HiSpeed Plasmid Maxi Kit.

(2-1) Method for Culturing and Subculturing HEK293

HEK293 (JCRB9068, NIBIO) was cultured in an incubator at 5% CO₂ and 37°C. using DMEM (11885-092, GIBCO) containing 10% FBS and1×Penicillin-Streptomycin (15140-122, GIBCO). Subculture was carried outas followings: The cells that reached 80 to 90% confluency were washedwith PBS(−), separated using 0.25% Trypsin-EDTA (25200-072, GIBCO),centrifuged, re-suspended in a fresh medium, and then seeded in CollagenType 1 Coated dish (4020-010, IWAKI) at a split ratio of 1:8 (culturedfor 3 days).

(2-2) Introduction of human FPRL1 and Gα15 expression vectors HEK293that reached 80 to 90% confluency was washed with PBS (−), separatedusing 0.25% Trypsin-EDTA, centrifuged, and re-suspended in a freshmedium excluding 1×Penicillin-Streptomycin. The cells were inoculated ina Collagen Type 1 coated 6-well plate (4810-010, IWAKI) to 5×10⁵cells/2.5 mL/well and cultured overnight. On the next day, human FPRL1and Gα15 expression vectors were introduced using Lipofectamine 2000transfection reagent (11668-019, Life technologies). First, the humanFPRL1 and Gα15 expression vectors were diluted with Opti-MEM I ReducedSerum Medium (31985-070, GIBCO) to 2 μg/250 μL/well and Lipofectamine2000 transfection reagent was diluted with Opti-MEM I Reduced SerumMedium to be 4 μL/250 μL/well. The vectors and reagent were softlydiffused, and incubated at room temperature for 5 minutes. The vectorsolution was mixed with Lipofectamine 2000 transfection reagent in equalamounts. In order to form a composite of the vectors and Lipofectamine2000 transfection reagent, the mixture was incubated at room temperaturefor 20 minutes, and added at 500 μL/well to the medium of inoculatedcells. The treated cells were cultured for 24 hours, inoculated inPoly-D-Lysine coated 96-well plate (356640, BD Biosciences) at a celldensity of 7×10⁴ cells/100 μL/well, and cultured for another 24 hours.The resultant cells were used in a measurement test of calciummobilization in the cells.

(3) Evaluation of Agonist Activity on Human FPRL1 (Test of CalciumMobilization in Cell)

An appropriate amount of each test compound was first weighed, anddissolved to 10⁻² M by addition of dimethyl sulfoxide (DMSO). Forcalculation of an EC₅₀ value for agonist activity, each compoundsolution was serially diluted with DMSO by 10-fold increments to makeeight solutions having a concentration of 10⁻² M to 10⁻⁹ M. The formedcompound solution having each concentration was diluted 100 times withan assay buffer that was contained in Fluo-4 NW Calcium Assay Kit(F36206, Life technologies), and dispensed in an amount of 100 μL into a96-well plate with a V-bottom shape. The plate dispensed with compoundsolutions was set in Flexstation (Molecular Devices, LLC.) untilmeasurement.

Subsequently, 10 mL of assay buffer and 100 μL of probenecid solution(dissolved by addition of 1 mL of assay buffer to a 250 mM stock) weresufficiently mixed and dissolved in Fluo-4 NW dye mix. The medium ofcells inoculated on the previous day was removed, the dissolved Fluo-4NW dye mix was added in an amount of 90 μL/well, and a reaction wascaused in the dark at 37° C. for 45 minutes. The cells after thereaction and chips for addition of the compound were set in Flexstation,and variation in fluorescence intensity over time after addition of thecompound was measured [amount of added compound=10 μL (finalconcentration: 10⁻⁵ M to 10⁻¹² M), excitation wavelength: 485 nm,measured wavelength: 525 nm, 1.5 sec×54 read]. A value was calculated bysubtracting a base value during addition of DMSO from the maximum valueof relative fluorescence unit, and analyzed. All the measurement datawere analyzed with Prism 4 that was a data analysis tool. As an EC₅₀value, a molar concentration that resulted in 50% maximum activation wascalculated. The EC₅₀ values of the resultant test compounds are shown inTables I to V.

TABLE I COMPOUND EC₅₀ TO BE TESTED (nM) EXAMPLE 1-1 0.09 EXAMPLE 1-20.09 EXAMPLE 1-3 2.57 EXAMPLE 1-5 2.88 EXAMPLE 1-6 0.20 EXAMPLE 1-7 0.22EXAMPLE 1-8 0.90 EXAMPLE 1-9 0.45 EXAMPLE 1-10 3.98

TABLE II COMPOUND EC₅₀ TO BE TESTED (nM) EXAMPLE 1-11 1.59 EXAMPLE 1-120.06 EXAMPLE 1-13 0.15 EXAMPLE 1-14 4.12 EXAMPLE 1-16 0.24 EXAMPLE 1-180.36 EXAMPLE 1-19 0.72 EXAMPLE 1-20 1.75 EXAMPLE 1-22 0.11 EXAMPLE 1-230.78 EXAMPLE 1-24 3.20 EXAMPLE 1-26 1.91 EXAMPLE 1-31 2.67 EXAMPLE 1-324.54 EXAMPLE 1-35 0.76 EXAMPLE 1-39 3.51 EXAMPLE 1-40 1.44 EXAMPLE 1-410.73 EXAMPLE 1-43 5.13 EXAMPLE 1-53 0.18 EXAMPLE 1-54 0.11 EXAMPLE 1-551.02 EXAMPLE 7-1 1.09 EXAMPLE 7-2 0.45 EXAMPLE 7-7 1.56 EXAMPLE 7-8 0.95EXAMPLE 7-9 0.16 EXAMPLE 8-1 0.29 EXAMPLE 9-1 0.86 EXAMPLE 12-1 0.13EXAMPLE 12-4 0.05 EXAMPLE 14-1 0.32 EXAMPLE 15-1A 0.01 EXAMPLE 15-1B1.99 EXAMPLE 17-1 0.11 EXAMPLE 18-1 2.36 EXAMPLE 19-1 0.21

TABLE III COMPOUND EC₅₀ TO BE TESTED (nM) EXAMPLE 20-1 0.47 EXAMPLE 21-10.04 EXAMPLE 23-1 0.09 EXAMPLE 24-1 0.09 EXAMPLE 25-1 0.04 EXAMPLE 26-10.07 EXAMPLE 27-1 3.14 EXAMPLE 31-1 1.94 EXAMPLE 32-1 0.13 EXAMPLE 32-20.03 EXAMPLE 32-3 0.05 EXAMPLE 32-4 0.17 EXAMPLE 32-5 0.03 EXAMPLE 32-60.37 EXAMPLE 33-1 1.14

TABLE IV COMPOUND EC₅₀ TO BE TESTED (nM) EXAMPLE 1-57 0.16 EXAMPLE 1-580.32 EXAMPLE 1-62 1.05 EXAMPLE 1-63 0.92 EXAMPLE 1-68 0.08 EXAMPLE 1-710.09 EXAMPLE 1-72 0.05 EXAMPLE 1-73 1.2 EXAMPLE 1-74 1.8 EXAMPLE 1-775.2 EXAMPLE 1-80 0.69 EXAMPLE 1-84 1.92 EXAMPLE 1-85 3.5 EXAMPLE 7-102.31 EXAMPLE 7-12 3.9 EXAMPLE 8-2 1.6 EXAMPLE 12-11 4.57 EXAMPLE 12-120.9 EXAMPLE 12-13 1.12 EXAMPLE 12-15 0.43 EXAMPLE 16-2 0.49 EXAMPLE 16-30.75 EXAMPLE 17-2 0.07 EXAMPLE 17-3 0.29 EXAMPLE 22-2 0.38 EXAMPLE 24-31.1 EXAMPLE 24-4 0.81 EXAMPLE 24-5 1.6 EXAMPLE 24-6 0.4 EXAMPLE 24-70.69 EXAMPLE 24-8 0.39 EXAMPLE 24-9 0.88 EXAMPLE 24-10 1.0 EXAMPLE 24-110.06 EXAMPLE 24-12 2.2 EXAMPLE 24-13 0.11 EXAMPLE 24-14 0.12 EXAMPLE24-15 0.03 EXAMPLE 24-16 0.15

TABLE V COMPOUND EC₅₀ TO BE TESTED (nM) EXAMPLE 24-17 0.02 EXAMPLE 24-180.03 EXAMPLE 24-19 0.33 EXAMPLE 24-20 0.15 EXAMPLE 24-21 0.45 EXAMPLE24-22 1.32 EXAMPLE 24-23 0.8 EXAMPLE 24-24 0.46 EXAMPLE 27-2 0.1 EXAMPLE28-4 1.64 EXAMPLE 28-5 1.42 EXAMPLE 32-8 0.44 EXAMPLE 32-9 0.3 EXAMPLE32-10 0.53 EXAMPLE 32-11 0.88 EXAMPLE 32-12 0.27 EXAMPLE 32-13 0.25EXAMPLE 32-14 0.82 EXAMPLE 32-15 0.27 EXAMPLE 32-16 0.54 EXAMPLE 32-170.57 EXAMPLE 32-18 0.54 EXAMPLE 32-19 0.13 EXAMPLE 32-20 2.86 EXAMPLE33-2 0.03

As seen from Tables I to V, the compounds (I) of the present inventionor pharmacologically acceptable salts thereof show a superior FPRL1agonist effect.

Test Example 2 Effect of Lipopolysaccharide Induction on NeutrophilicInfiltration in Mouse Lung

A compound to be tested was orally administrated to a mouse (BALB/c,male), and after 30 minutes, the mouse was placed in a plasticcontainer. Lipopolysaccharide (0.3 mg/mL) dissolved in physiologicalsaline was aerosolized with an ultrasonic wave nebulizer (NE-U17, OMRONCorporation), and exposed to the mouse for 10 minutes. After 5 hours,the anesthetized mouse was sacrificed by exsanguination. A cannula wasinserted in the respiratory tract and bronchoalveolar lavage (BAL) with1 mL of 0.85% NaCl liquid containing 0.4% sodium citrate was carriedout. This operation was repeated 3 times, to obtain a BAL fluid. The BALfluid was centrifuged at 4° C. and ×200 g for 5 minutes, and the pelletwas suspended in a physiological saline containing 0.1% BSA. The numberof white blood cells was counted using Turks solution with a microscope,and the total white blood cell count was calculated. The white bloodcells were fixed on a glass slide using Cytospin 3 (Thermo BioAnalysisJapan K. K.). The cells were stained with Diff-Quik (SYSMEXINTERNATIONAL REAGENTS CO., LTD.), and the number thereof was countedwith a microscope, and the neutrophil ratio was calculated. Theneutrophil ratio was multiplied by the total white blood cell count tocalculate the total neutrophil count. An effect of the compound to betested represents a percentage (%) of suppression ratio relative to theneutrophil count in a control. The suppression ratios of the resultanttest compounds are shown in Tables VI to VIII.

TABLE VI COMPOUND SUPPRESSION DOZE TO BE TESTED RATIO (mg/kg) EXAMPLE1-1 95.1 1 EXAMPLE 1-2 99.2 1 EXAMPLE 1-7 96.9 1 EXAMPLE 1-9 98.5 3

TABLE VII COMPOUND SUPPRESSION DOZE TO BE TESTED RATIO (mg/kg) EXAMPLE1-12 96.8 1 EXAMPLE 1-16 95.8 1 EXAMPLE 1-18 98.3 1 EXAMPLE 1-22 93.1 1EXAMPLE 1-23 98.9 3 EXAMPLE 1-31 69.7 1 EXAMPLE 1-53 78.9 1 EXAMPLE 1-5498.6 3 EXAMPLE 1-55 83.7 3 EXAMPLE 12-1 97.4 3 EXAMPLE 25-1 99.1 3EXAMPLE 26-1 99.6 1 EXAMPLE 32-1 99.0 3 EXAMPLE 32-3 99.1 3 EXAMPLE 32-599.8 1

TABLE VIII COMPOUND SUPPRESSION DOZE TO BE TESTED RATIO (%) (mg/kg)EXAMPLE 1-68 85.6 3 EXAMPLE 1-71 79.7 3 EXAMPLE 1-72 93.3 3 EXAMPLE 1-8499.2 1 EXAMPLE 7-2 87.7 1 EXAMPLE 9-1 57.0 3 EXAMPLE 32-12 96.8 1

As seen from Tables VI to VIII, the compounds (I) of the presentinvention or pharmacologically acceptable salts thereof had a superioraction of suppressing neutrophil infiltration.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior action ofsuppressing neutrophil infiltration due to a superior FPRL1 agonisteffect, and therefore is useful as a therapeutic or prophylactic agentfor inflammatory disease, chronic airway diseases, cancers, septicemia,allergic symptoms, HIV retrovirus infection, circulatory disorders,neuroinflammation, nervous disorders, pains, prion diseases,amyloidosis, immune disorders and the like.

Sequence Listing Free Text <Sequence Listing 1>

SEQ ID NO: 1 is a sequence of a forward primer used for amplification ofDNA of human FPRL1 (SEQ ID NO: 3), and is supplemented with a Hind IIIrecognition site.

<Sequence Listing 2>

SEQ ID NO: 2 is a sequence of a reverse primer used for amplification ofDNA of human FPRL1 (SEQ ID NO: 3), and is supplemented with an XhoIrecognition site.

<Sequence Listing 3>

SEQ ID NO: 3 is an open reading frame (ORF) of human FPRL1, and is a DNAsequence of a site translated into an amino acid.

<Sequence Listing 4>

SEQ ID NO: 4 is a sequence of a forward primer used for amplification ofDNA of human Gα15 (SEQ ID NO: 6), and is supplemented with a Hind IIIrecognition site.

<Sequence Listing 5>

SEQ ID NO: 5 is a sequence of a reverse primer used for amplification ofDNA of human Gα15 (SEQ ID NO: 6), and is supplemented with an XhoIrecognition site.

<Sequence Listing 6>

SEQ ID NO: 6 is an open reading frame (ORF) of human Gα15, and is a DNAsequence of a site translated into an amino acid.

1. A compound, or a pharmacologically acceptable salt thereof, whereinsaid compound is:(−)-1-(2,4-difluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(7-fluorochroman-6-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-methylsulfonylphenyl)urea;(−)-1-(benzo[d][1,3]dioxole-5-yl)-3-[(3R*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyrimidin-4-yl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyridin-2-yl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyridin-3-yl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyrimidin-5-yl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(pyrazin-2-yl)urea;(−)-1-(benzo[d]thiazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-(benzo[d]oxazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(5-methylisoxazol-3-yl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(2-fluorophenyl)urea;1-[(3S*,4R*)-4-(4-ethyl-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(3-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(2-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(+)-1-[(3R*,4S*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-fluorophenyl)-3-[(3R*,4S*,5S*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-fluorophenyl)-3-[(3R*,4S*,5R*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-fluorophenyl)-3-[(3R*,4S*)-4-(5-methoxythiophen-2-yl)-2-oxopyrrolidin-3-yl]urea;(+)-1-{(3R*,4S*)-4-[4-(difluoromethoxy)phenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;(±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;(±)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(±)-trans-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;(+)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]urea;(−)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]urea;(+)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea;(−)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.4]nonan-3-yl]urea;(+)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea;(−)-trans-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxo-1-azaspiro[4.5]decan-3-yl]urea;(−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylsulfinylphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methylsulfonylphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[4-(tert-butyl)phenyl]-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}benzoicacid ethyl ester;(−)-1-[(1,1′-biphenyl)-4-yl]-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-(4-acetylphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3,4-difluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(hydroxymethyl)phenyl]urea;(−)-4-{3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]ureido}-N-methylbenzamide;2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid ethyl ester;2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionicacid ethyl ester;(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid ethyl ester (isomer A);(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}propionicacid ethyl ester (isomer B);(+)-trans-1-(4-chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-trans-1-(4-chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}aceticacid;2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-2-methylpropionicacid;(+)-1-(4-fluorophenyl)-3-[(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}-N,N-dimethylbenzamide;(−)-3,5-difluoro-4-{(3R*,4S*)-4-[3-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-yl}-N-methylbenzamide;(−)-1-[(3S*,4R*)-4-(4-cyano-2,6-difluorophenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(+)-1-(4-fluorophenyl)-3-[(3R*,4S*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yl]urea;1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-hydroxyphenyl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-methylisothiazol-5-yl)urea;(−)-1-(4-cyclopropylphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-[4-(trifluoromethyl)phenyl]urea;(−)-1-(4-chloro-3-hydroxyphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;1-(4-cyano-3-hydroxyphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;1-{(3S*,4R*)-4-[4-(difluoromethoxy)-2,6-difluorophenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(6-fluorobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;1-[(3S*,4R*)-4-(4,6-difluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-(benzo[b]thiophene-2-yl)-3-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-ethylphenyl)urea;(−)-1-(3-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-(5-chlorothiophen-2-yl)-3-[(3S*,4R*)-4-(3-fluoro-5-methoxypyridine-2-yl)-2-oxopyrrolidin-3-yl]urea;(−)-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-chlorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-fluorophenyl)-3-[4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(+)-1-(4-fluorophenyl)-3-[l-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea;(−)-2-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}aceticacid;(−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}aceticacid;(−)-2-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-N-methylacetamide;(−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}acetamide;(−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-2-methylpropanoicacid;(−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;(−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;(−)-1-(benzo[b]thiophene-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(p-tolyl)urea;(−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-(benzo[b]thiophene-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxo-1-propylpyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-1-benzyl-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxo-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-[(methylsulfonyl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;(−)-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}methanesulfonamide;(−)-2-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}aceticacid ethyl ester;(−)-1-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-[(5-methyloxazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;(−)-1-{(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}aceticacid ethyl ester;(−)-2-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-3-[3-(4-fluorophenyl)ureido]-2-oxopyrrolidin-1-yl}-2-methylpropanoicacid ethyl ester;(−)-1-[(3S*,4R*)-1-(cyclopropylmethyl)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-1-(cyanomethyl)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-{(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methoxy-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;1-[(3S*,4R*)-4-(2,6-difluoro-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(p-tolyl)urea;(−)-1-(4-cyanophenyl)-3-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]urea;(−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]urea;(−)-1-(benzo[b]thiophen-2-yl)-3-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]urea;(−)-1-(4-cyanophenyl)-3-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}urea;(−)-1-(6-chloropyridin-3-yl)-3-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}urea;(−)-1-(benzo[b]thiophen-2-yl)-3-{(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}urea;(−)-1-{(3R*,4S*)-3-(2,6-difluoro-4-methoxyphenyl)-5-[(1-methyl-1H-pyrazol-3-yl)amino]-3,4-dihydro-2H-pyrrole-4-yl}-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(morpholinoimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea;1-[(3R*,4S*)-3-(2,6-difluoro-4-methoxyphenyl)-5-(phenylamino)-3,4-dihydro-2H-pyrrole-4-yl]-3-(4-fluorophenyl)urea;(−)-1-((3S*,4R*,Z)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl)-3-(4-fluorophenyl)urea;3-((Z)-{(3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-3-[3-(4-fluorophenyl)ureido]pyrrolidin-2-ylidene}amino)propanoicacid ethyl ester;(−)-1-((3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(hydroxyimino)pyrrolidin-3-yl)-3-(4-fluorophenyl)urea;(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-ethynylphenyl)urea;or(−)-1-{(3S*,4R*)-4-[2,6-difluoro-4-(methylamino)phenyl]-2-oxopyrrolidin-3-yl}-3-(4-fluorophenyl)urea.2. A pharmaceutical composition comprising, as an active ingredient, acompound according to claim 1 or a pharmacologically acceptable saltthereof.
 3. A method of agonizing FPRL1 comprising contacting FPRL1 witha compound according to claim 1 or a pharmacologically acceptable saltthereof.
 4. A method of treating an inflammatory disease, a chronicairway disease, cancer, septicemia, a circulatory disorder,neuroinflammation, a nervous disorder, pain, aprion disease,amyloidosis, or an immune disorder in a patient in need of treatment,comprising administering to the patient a therapeutically effectiveamount of the compound according to claim 1 or a pharmacologicallyacceptable salt thereof.
 5. The method of claim 4 wherein the immunedisorder is an allergic symptom or HIV retrovirus infection.